Fight Aging!

Over at the SENS Foundation, you'll find fairly detailed commentary from Michael Rae on the recent news of progress towards a viable therapy for the rare accelerated aging condition progeria. As I've noted in recent years, one of the things learned about the mechanisms of progeria is that they seem to be a greatly exaggerated version of processes that happen in all of us - in the same sense that the runaway mechanisms of Alzheimer's or Parkinson's disease (and many other age-related conditions) take place at low levels in all of us.

So should we do more than keep a weather eye on progeria research? Probably not:

All of us at SENS Research Foundation are inspired by the rapid progress that was made against this tragic disease ... However, it is also important not to read too much into this apparent advance in regards to its implications for the development of new medicines against the diseases and disabilities of aging. In particular, the common characterization of HGPS "progeria" as a disease of "premature aging" leads some to expect that this research has direct implications for the development of rejuvenation biotechnologies, targeting the damage and disabilities of aging.

It is true that the splicing defect responsible for formation of progerin is sporadically active in wild-type cells, and that number of cells in which progerin is present and the level at which it appears do appear to rise with aging. However, such cells are rare enough, and their progerin levels low enough, as to seem highly unlikely to meaningfully contribute to tissue dysfunction with aging, at least within the bounds of a currently-normal lifespan. Additionally, there is evidence that progerin can be turned over in the nuclear lamina, and the causal relationship between the higher prevalence of progerin in aging cells and cellular senescence or disease are not clear, leaving open the possiblity that repair of well-established forms of aging damage may in turn lead to the reversal or obviation of this phenomenon.

Notably, the need to remove "senescent" cells as part of a comprehensive panel of rejuvenation biotechnologies is already clear from first principles, and its potential to ameliorate aspects the frailty and disability of aging has been demonstrated in proof-of-concept rejuvenation research, rendering the specific role of progerin in the process moot. That is, removing "senescent" cells is essential whether progerin accumulation is a cause or a consequence of cellular senescence, and will be equally effective as a regenerative medical therapy against age-related disability in either case.

It is absolutely the case that we'd expect new and interesting challenges to show up once people are living well past the normal human life span. We'd expect to see forms of biological damage that are generally irrelevant over the course of a century turn out to be lethal at two centuries, for example - perhaps nuclear DNA damage, perhaps progerin accumulation, perhaps the fact that some important macromolecules are never normally replaced, perhaps more obscure aggregated metabolic waste products. So largely things we presently know about, can presently ignore, and will have a great deal of time to work on should it turn out to be problem down the line.

It is thought that size in humans relates to life expectancy via aspects of metabolism such as growth hormone - less growth hormone means a smaller size but longer life in mammal species. Ames dwarf mice are an example of this taken to an extreme through genetic engineering, lacking growth hormone but living more than 60% longer than their peers.

From an evolutionary perspective, an abundance of food and good health in early life or gestation is thought to trigger a more aggressive front-loading of growth and fertility - which comes at the cost of faster decline once an individual is beyond their reproductive lifespan:

Sardinians have been studied extensively looking for clue to long lifespan. In the current study researchers analyzed the role of a person's height in their eventual lifespan. The researchers analyzed the height of men when they entered the military at age 20 between the years of 1866 and 1915. A total of 685 subjects were analysed. These heights were then related to the persons eventual age at death. It was found that shorter people (shorter than 161.1 cm) lived significantly longer on average than taller people (taller 161.1cm). Furthermore at age 70, taller people lived on average 2 years less than shorter people. At age 70 each quarter inch of height reduced lifespan by one year.

The authors write: In conclusion, shorter people and taller people exhibit differences in longevity. Although a tall body generally reflects abundant nutrition and good living conditions during the growth period, this height has negative ramifications as well. Biological mechanisms indicate that a larger body places greater stress on cells, tissues, and organs, which can reduce longevity.

Link: http://extremelongevity.net/2012/09/26/shorter-people-live-longer/

Telomeres are the protective caps at the end of chromosomes. They shorten with cell division, and so are part of the clock which decides when a cell reaches the Hayflick limit and ceases dividing. There is much more to it than this, however: telomere length across all the cells in a piece of living tissue is dynamic, as there are processes that lengthen telomeres as well - such as the activity of telomerase.

In general average telomere length erodes with age, reflecting the progressive breakdown of the body's ability to maintain itself - but this proceeds quite differently in different tissues and different species. It can even be reversed in the short term if the health of an individual improves, though in the long term the overall progression is still downhill.

Shorter average telomere length has been correlated with measures of health in statistical studies, but data allowing prediction of longevity for an individual has proven elusive to date. Here, however, a more sophisticated measure of telomere dynamics is show to be predictive of life span in individual mice:

Aberrantly short telomeres result in decreased longevity in both humans and mice with defective telomere maintenance. Normal populations of humans and mice present high interindividual variation in telomere length, but it is unknown whether this is associated with their lifespan potential. To address this issue, we performed a longitudinal telomere length study along the lifespan of wild-type and transgenic telomerase reverse transcriptase mice.

We found that mouse telomeres shorten ∼100 times faster than human telomeres. Importantly, the rate of increase in the percentage of short telomeres, rather than the rate of telomere shortening per month, was a significant predictor of lifespan in both mouse cohorts, and those individuals who showed a higher rate of increase in the percentage of short telomeres were also the ones with a shorter lifespan. These findings demonstrate that short telomeres have a direct impact on longevity in mammals, and they highlight the importance of performing longitudinal telomere studies to predict longevity.

Link: http://dx.doi.org/10.1016/j.celrep.2012.08.023

Based on what we know today, inhibition of myostatin in muscle tissue looks like one of the few win-win, all-round beneficial alterations that could be made to human metabolism. Lacking myostatin, a mutation that occurs naturally in very rare cases, an individual has much more muscle, less fat, and resistance to some of the common issues that occur with aging - though it is unclear as to how much of that latter benefit stems from an extended ability to exercise and the comparative lack of visceral fat. A sedentary lifestyle and excess visceral fat are both very bad for you over the long term, causing a shorter life expectancy and greater risk of many forms of age-related disease and disability.

Myostatin inhibitors are under investigation as the potential basis for therapies to slow or reverse the progressive loss of muscle mass and strength that occurs with age, a condition known as sarcopenia. The physical frailty of aging is something of a self-reinforcing downward spiral, and addressing even just the muscle strength component of this decline could bring noteworthy benefits.

Research into myostatin dovetails with research into the decline of stem cells with aging, such as the satellite cells in muscle. The fading activity of the satellite stem cell populations that support muscle tissue is thought to be one contributing cause of sarcopenia. Others range from chronic inflammation through to a progressive inability to make proper use of leucine in the diet.

There is no claim that inhibition of myostatin will address the root causes of sarcopenia: it is more a matter of dialing up the "build muscle" switch to levels that do not normally occur as a way of compensation. As a method of doing so it seems to cause no undue complications - which is a good thing and sadly very rare due to the overwhelming complexity of our biology - but it is nonethless far from ideal. In that ideal world, we'd want all therapies (for aging or otherwise) to tackle root causes rather that patch over symptoms, but sometimes you take what you can get.

In any case, here is an update from the world of myostatin research with some additional information on how things tie together under the hood:

Blocking myostatin function in normal mice causes them to bulk up by 25 to 50 percent. What is not known is which cells receive and react to the myostatin signal. Current suspects include satellite cells and muscle cells themselves. In this latest study, researchers used three approaches to figure out whether satellite cells are required for myostatin activity. They first looked at specially bred mice with severe defects in either satellite cell function or number. When they used drugs or genetic engineering to block myostatin function in both types of mice, muscle mass still increased significantly compared to that seen in mice with normal satellite cell function, suggesting that myostatin is able to act, at least partially, without full satellite cell function.

...

to further confirm their theory that myostatin acts primarily through muscle cells and not satellite cells, the team engineered mice with muscle cells lacking a protein receptor that binds to myostatin. If satellite cells harbor most of the myostatin receptors, removal of receptors in muscle cells should not alter myostatin activity, and should result in muscles of normal girth. Instead, what the researchers saw was a moderate, but statistically significant, increase in muscle mass. The evidence once again, they said, suggested that muscle cells are themselves important receivers of myostatin signals. ... since the results give no evidence that satellite cells are of primary importance to the myostatin pathway, even patients with low muscle mass due to compromised satellite cell function may be able to rebuild some of their muscle tone through drug therapy that blocks myostatin activity.

"Everybody loses muscle mass as they age, and the most popular explanation is that this occurs as a result of satellite cell loss. If you block the myostatin pathway, can you increase muscle mass, mobility and independence for our aging population? [Our] results in mice suggest that, indeed, this strategy may be a way to get around the satellite cell problem."

So myostatin inhibition continues to look like a promising form of patch, in that it fails to address root causes but nonetheless produces meaningful benefits with few if any unwanted side-effects - which is more than can be said for many other forms of patch either in operation or under development in the world of medicine.

Researchers here investigate another portion of the mechanisms of metabolism that are influenced by calorie restriction and many of the known longevity genes. This sort of discovery helps to fill in a very complicated landscape of intertwining effects and controllers of effects - at some point in the not too distant future the research community will be able to set out a complete map of how all of the longevity genes and known ways to extend life in laboratory animals relate to one another and work through an overlapping set of mechanisms:

In this study, we demonstrated that the overexpression of fatty-acid-β-oxidation-related genes extended median and maximum lifespan [in flies] and increased stress resistance, suggesting that the level of fatty-acid β-oxidation regulates lifespan.

Consistent with our results, many investigations have suggested fatty-acid β-oxidation as a lifespan determinant. One of the well-known longevity-candidate genes, AMPK reportedly regulates fatty-acid synthesis and oxidation. Moreover, calorie restriction and [insulin/insulin-like growth factor (IGF) signaling (IIS)] have been reported to promote fatty-acid β-oxidation. In addition, enigma mutant, which exhibits oxidative stress resistance and a longevity phenotype, was found to encode a fatty-acid-β-oxidation related enzyme. ... However, the present study is the first to provide direct evidence that the modulation of fatty-acid-β-oxidation components extends lifespan.

Our data showed that lifespan extension by dietary restriction decreased with the overexpression of fatty-acid β-oxidation-related genes, indicating that lifespan extension by fatty-acid-β-oxidation components is associated with dietary restriction. It was previously reported that calorie restriction increased whole-body-fat oxidation. Energy deprivation subsequent to calorie restriction activates AMPK, which subsequently enables the increase of fatty-acid oxidation necessary to utilize the energy resource. These findings suggested that fatty acid oxidation and dietary restriction are related by same underlying mechanisms.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3446750/

We mammals just can't regenerate as well as lower animals - but we all evolved from the same ancestors, so the suspicion is that we might retain at least some of the necessary mechanisms to regrow organs and limbs, just buried and inactive. Some studies have uncovered possible hints of this: you might recall the gene engineered MRL mice that have superior regenerative abilities due to inactivation of p21, for example.

Here, researchers note the discovery of superior natural regenerative abilities in a rodent species - which should hopefully lead to some further insight into how we might make humans regenerate more capably:

Two species of African spiny mouse have been caught at something no other mammal is known to do - completely regenerating damaged tissue. ... Acomys kempi and Acomys percivali [have] skin that is brittle and easily torn, which helps them to escape predators by jettisoning patches of their skin when caught or bitten. ... whereas normal laboratory mice (Mus musculus) grow scar tissue when their skin is removed, African spiny mice can regrow complete suites of hair follicles, skin, sweat glands, fur and even cartilage.

Tissue regeneration has not been seen in mammals before, but it is common in crustaceans, insects, reptiles and amphibians. Some lizards can regrow only their tails, whereas some salamanders can regenerate entire limbs, complete with bones and muscle.

The researchers say that their next step will be to work out the molecular mechanisms and genetic circuits that direct the regeneration process. It's unlikely that these mice have evolved an entirely new method of regrowing tissue ... Rather, the genes that direct regeneration in salamanders are probably switched off in mammals, but have been switched back on in African spiny mice. ... By looking at the common genetic blueprints that exist across vertebrates, we hope to find the ones that we could activate in humans. We just need to figure out how to dial the process in mammals back to do something the entire system already knows how to do.

Link: http://www.nature.com/news/african-spiny-mice-can-regrow-lost-skin-1.11488

The various fibroblast growth factors are known to be involved in stem cell activity, and thus in regeneration and embryonic development. As is usual in these matters the picture is complex and far from fully understood when it comes to what happens to stem cells and their regulation in aging. Nonetheless, inroads are being made into selectively slowing or reversing the decline of stem cell activity with age - which brings with it the progressive failure and frailty of tissues that become inadequately maintained.

This is all very necessary for the field of regenerative medicine, as most of the medical conditions that stem cell science is best placed to tackle are age-related. If therapies are to be based on the use and manipulation of stem cells, then researchers will have to understand how to minimize or remove the deleterious effects that an age-damaged metabolism has on these cells.

The modest advance for today is this: scientists have managed to slow stem cell decline in muscles by inhibiting fibroblast growth factor 2 (FGF2), and in the course of doing so might have shed some more light on the debated question of what happens to stem cells in aging - why exactly it is that their activity declines.

Inadequate cellular rest may explain effects of aging on muscles

Rare muscle stem cells are located inside each skeletal muscle of the body. Also called satellite cells, due to their position on the surface of the muscle fibers they serve and protect, these cells are essential to maintaining the capacity of muscles to regenerate. Satellite cells are able to generate new, differentiated muscle cells while keeping their identity as stem cells, retaining the ability to maintain and repair muscle tissue. Normally in a resting or dormant state, satellite cells respond rapidly to repair injured tissues. The current study finds that aging muscle stem cells lose their ability to maintain a dormant state, so that when called upon to repair injured muscle, they are unable to mount an adequate response. ... Just as it is important for athletes to build recovery time into their training schedules, stem cells also need time to recuperate, but we found that aged stem cells recuperate less often. We were surprised to find that the events prior to muscle regeneration had a major influence on regenerative potential.

In a series of experiments in mice, the authors found that a developmental protein called fibroblast growth factor-2 (FGF2) is elevated in the aging muscle stem cell microenvironment and drives stem cells out of the dormant state. Satellite cells that are forced to replicate lose the ability to maintain their identity as stem cells, reducing the stem cell population.

The authors also found that blocking the age-related increase in FGF signaling both in aged satellite cells or in the cellular microenvironment protected against stem cell loss, maintained stem cell renewal during aging and dramatically improved the ability of aged muscle tissue to repair itself.

This seems like a promising demonstration of what can be achieved as we learn more of the mechanisms that steer stem cell behavior. That said, it is probably the case that any widespread use of therapies to keep stem cells in circulation would have to be matched by an increased vigilance and ability to combat cancer. It is generally thought that declining stem cell activity is an evolved balance between loss of tissue integrity and risk of cancer. More stem cell activity in later life would suggest a raised chance of cancer, if all other things are equal.

Of course we'd like to do far better than "all other things are equal." The proposed future of medicine is one of damage repair at all levels: fixing all the broken proteins, removing all the lingering metabolic waste products, culling senescent cells, and so forth. Sorting out the stem cell issue is just one of many parts to a general rejuvenation biotechnology toolkit.

There are many genes associated with longevity, but one of the present challenges in this research is that few such correlations seem to exist in multiple populations - implying that there is a very large set of individually small contributions from our genes, and that different lineages and lifestyles have significantly different maps of genes to longevity:

Men and women have a different life expectancy. Not unexpectedly, several genes involved in lifespan determination have been found to influence the probability of achieving longevity differently in men and women. This investigation examines the association between longevity and polymorphisms of follicle-stimulating hormone receptor (FSHR, Asn680Ser polymorphism) and peroxisome proliferator-activated receptor gamma (PPARG, Pro12Ala polymorphism), two genes that previous investigations suggested may exert a gender-specific influence on human longevity.

A sample of 277 individuals (mean age: 82.9±5.7years) was recruited in 2000. Based on mortality data collected in 2009, the sample was divided into two groups of subjects surviving over 90 years (long-lived) or not (controls). The frequency of FSHR 680 Ser/Ser genotype was significantly higher in the sample of long-lived women compared to controls, indicating that FSHR 680 Ser/Ser genotype may favor survival to more than 90 years of age only in women. In contrast, the frequency of PPARG Pro/Ala genotype was significantly higher in the sample of male subjects who died before 90 years than in the long-lived, suggesting that carrying PPARG Pro/Ala genotype may prevent the attainment of advanced age only in men.

We then searched the literature for studies reporting a differential role for the genetic component in male and female longevity; to do this, we selected longevity genes with a gender-specific effect. A review of the studies showed that genetic factors tend to have a greater relevance in determining longevity in men than in women.

Link: http://www.ncbi.nlm.nih.gov/pubmed/22985084

A paper that compares genealogical records of Korean eunuchs with their intact peers from past centuries has been doing the rounds, with the data showing a higher life span for the eunuchs. However, there is considerable skepticism from the rest of the research community - there are any number of ways to sneak in a bias towards longer-lived, more robust individuals: how the data came into being; how it is analyzed; how the eunuchs originally came into their position; their life style differences; and so forth.

So it is hard to see any good way to discuss the role of male hormones in relation to this data, given all of the potential confounding factors not addressed by the authors. For example, only 81 of 385 recorded eunuchs had enough information present in the genealogy to pin down a life span. This alone could contain a bias towards longer-lived, more active, or more privileged individuals: there is no reason to think that these 81 are representative. But this is the nature of scientific research - individual research results have to be read skeptically and in the broader context of their field:

Historically, eunuchs have been employed as guards and servants in harems across the Middle East and Asia. The Imperial court of the Korean Chosun Dynasty (1392-1910) also had eunuchs. Eunuchs of the Chosun Dynasty lived with privileges: Korean eunuchs were conferred with official ranks and were legally allowed to marry, a practice that was officially banned in the Chinese Empire. In addition, married couples were also entitled to have children by adopting castrated boys or normal girls. The boys lost their reproductive organs in accidents, or they underwent deliberate castration to gain access to the palace before becoming a teenager. ... Several studies have described the long-term consequences of castration in eunuchs, but there have been no data on the lifespan of eunuchs.

We examined the lifespan of Korean eunuchs by analyzing the Yang-Se-Gye-Bo - a genealogy record of Korean eunuchs. To our knowledge, this is the only record of eunuch-family histories in the world. ... The Yang-Se-Gye-Bo contains the records of 385 eunuchs. From these records, the lifespans of 81 eunuchs could be identified. The average lifespan of this group was 70.0 ± 1.76 years. As lifespan is affected by genetic and socio-economic factors, we compared the lifespan of eunuchs with the lifespan of men from three non-eunuch families of similar social status, who lived during the same time periods. ... The average lifespan of eunuchs [was] 14.4-19.1 years longer than the lifespan of non-castrated men of similar socio-economic status. Our study supports the idea that male sex hormones decrease the lifespan of men.

Link: http://www.cell.com/current-biology/fulltext/S0960-9822%2812%2900712-9

Our mitochondria are responsible for a goodly portion of degenerative aging. Mitochondria are the power plants of the cell, responsible for building the chemical energy stores used to power cellular operations. Each mitochondrion is basically a wrapper membrane that encloses a fluid bag of protein machines, and every cell has a swarm of them floating around inside it. Mitochondria are the evolved descendants of symbiotic bacteria, and they still act much like bacteria in many ways: multiplying by division and promiscuously swapping protein machinery with one another, for example. They also have their own DNA, separate from the DNA in the cell nucleus, that encodes many of the proteins vital to their operation.

This DNA is where the problems start. It's sitting right next door to a power plant that generates all sorts of reactive byproducts - and so mitochondrial DNA is far more prone to harmful mutations than the DNA in the cell nucleus. The DNA repair mechanisms for mitochondria are worse as well.

Now in the case of most significant mitochondrial DNA damage caused this way, the damaged mitochondrion will eventually be broken down, destroyed by the cell's quality control mechanisms, and replaced through fission of a working mitochondrion. Unfortunately there are certain forms of damage that subvert the cell's ability to detect the resulting faulty operation of the mitochondrion - so it is left alone, to divide and create more faulty mitochondria. Once that happens, a cell is doomed to be overtaken by broken mitochondria and then fall into a maladaptive state of operation that exports harmful, reactive compounds into surrounding tissue.

With enough of that going on, real harm starts to accrue to organs and biological systems in the body: i.e. a part of why you become aged is because a small but significant portion of your cells are filled with broken mitochondria, and as a consequence are acting badly and causing damage. Aging is nothing more than an accumulation of damage, after all.

All of this is why research into ways to repair, replace, or otherwise deal with damaged mitochondria is so important. The research community is on the verge of being able to achieve these goals, and any resulting therapy will likely have a large impact on human aging - it will be a concrete step towards rejuvenation of the old, providing a way to remove this one signification contribution to degenerative aging.

Yesterday I was pointed towards some exciting research results in which scientists demonstrate that cells will ingest and adopt appropriately engineered mitochondria, adding them to the existing herd without the need for any intervention beyond placing the engineered mitochondria into the same cell culture. The researchers are calling their process peptide-mediated mitochondrial delivery:

Functional Recovery of Human Cells [via] Peptide-Mediated Mitochondrial Delivery

We explored the feasibility of mitochondrial therapy using the cell-penetrating peptide Pep-1 to transfer mitochondrial DNA (mtDNA) between cells ... Pep-1-conjugated wild-type mitochondria isolated from parent cybrid cells incorporating a mitochondria-specific tag were used as donors for mitochondrial delivery ... Forty-eight hours later, translocation of Pep-1-labelled mitochondria into the mitochondrial regions of [host] cells was observed (delivery efficiencies of 77.48 and 82.96%, respectively). These internalized mitochondria were maintained for at least 15 days in both cell types and were accompanied by mitochondrial function recovery

As you can imagine, this immediately leads one to think in terms of an infusion-type therapy, where a fluid solution containing hordes of mitochondria can be introduced into tissues and be taken up into cells. The mitochondria themselves can be cultivated like bacteria from a sample from the patient, which is gene engineered to fix issues such as genetic diseases caused by mutations in mitochondrial DNA - or they can be from a donor.

In a more liberated, free-wheeling future, this sort of approach might be widely used to swap out the mitochondria you are born with for a better set. It is already the case that some mitochondrial lineages have been shown to be better than others in terms of functionality and durability. Looking further ahead, we might see optimal mitochondria: artificially created biological machines that do the same job, but designed to remove the issues that cause harm and aging in the natural version.

The ability to insert new mitochondria is a viable approach for genetic diseases, where the patient's lineage is damaged. The new fully functional mitochondria will dilute the effects of the established mitochondria, and may largely replace them with time. Thinking on this points out the major issue with wholesale mitochondrial replacement, however: it's not the case that functional mitochondria will necessarily out-compete non-functional mitochondria within a cell over the long haul. Consider that the situation becomes something like competition between bacterial strains in an enclosed environment: whichever strain has the advantage will eventually win out. This picture is complicated by the fact that mitochondria swap components among themselves, but still seems to be a useful model when thinking about results.

For the genetic disease sufferers, it should be comforting to see that the researchers demonstrated repair of cells with broken mitochondria by inserting working mitochondria. For aging, however, the picture is less certain. After all, the problems caused by damaged mitochondria in aging occur because these damaged cellular components have an advantage to survival - they are damaged in a way that evades the surveillance mechanisms designed to weed out broken, harmful mitochondria. So it isn't clear that throwing in a bunch of working mitochondria will help all that much; one might imagine a short-lived benefit, but then you're right back to where you were before.

Which is not to say that people shouldn't try this. I say run up some old flies or nematode worms and infuse them with fresh new mitochondria, see what happens. A study in nematodes in particular should proceed fairly straightforwardly from being able to do this in cell cultures.

Technology platforms for the delivery of therapies to the mitochondria in our cells are both important and showing signs of progress. There are any number of ways in which we would like to manipulate our mitochondria, most importantly to repair or work around damage to their DNA because that is one of the contributing causes of aging. Given a general method for placing any therapy inside mitochondria we should see more development and experimentation in ways to repair them. Here, researchers "have refined the nanoparticle drug delivery process further by using nanoparticles to deliver drugs to a specific organelle within cells. By targeting mitochondria, 'the powerhouse of cells,' the researchers increased the effectiveness of mitochondria-acting therapeutics used to treat cancer, Alzheimer's disease and obesity in studies conducted with cultured cells. ... The mitochondrion is a complex organelle that is very difficult to reach, but these nanoparticles are engineered so that they do the right job in the right place. [Researchers] used a biodegradable, FDA-approved polymer to fabricate their nanoparticles and then used the particles to encapsulate and test drugs that treat a variety of conditions. ... getting drugs to the mitochondria is no simple feat. Upon entering cells, nanoparticles enter a sorting center known as the endosome. The first thing [researchers] had to demonstrate was that the nanoparticles escape from the endosome and don't end up in the cells' disposal center, the lysosome. The mitochondria itself is protected by two membranes separated by an interstitial space. The outer membrane only permits molecules of a certain size to pass through, while the inner membrane only permits molecules of a given range of charges to pass. The researchers constructed a library of nanoparticles and tested them until they identified the optimum size range - 64 to 80 nanometers, or approximately 1,000 times finer than the width of a human hair - and an optimum surface charge, plus 34 millivolts. ... the components they used to create the nanoparticles are FDA approved and that their methods are highly reproducible and therefore have the potential to be translated into clinical settings. The researchers are currently testing their targeted delivery system in rodents and say that preliminary results are promising."

Link: http://www.kurzweilai.net/delivery-drugs-via-nanoparticles-to-target-mitochondria

Researchers here show data resulting from a therapy targeting the underlying cause of progeria. Accelerated aging conditions are extremely rare, but this is interesting to the rest of us because the same mechanisms that run wild in progeria sufferers apparently occur in a minor way during normal aging - so a cure for progeria might have some utility for the rest of us as well: "Results of the first-ever clinical drug trial for children with Progeria, a rare, fatal 'rapid-aging' disease, demonstrate the efficacy of a farnesyltransferase inhibitor (FTI), a drug originally developed to treat cancer. The clinical trial results, completed only six years after scientists identified the cause of Progeria, included significant improvements in weight gain, bone structure and, most importantly, the cardiovascular system ... Twenty-eight children from sixteen countries participated in the two-and-a-half year drug trial, representing 75 percent of known Progeria cases worldwide at the time the trial began. Of those, 26 are children with the classic form of Progeria. ... One in three children demonstrated a greater than 50 percent increase in annual rate of weight gain or switched from weight loss to weight gain, due to increased muscle and bone mass. ... On average, skeletal rigidity (which was highly abnormal at trial initiation) improved to normal levels after FTI treatment. ... Arterial stiffness, strongly associated with atherosclerosis in the general aging population, decreased by 35 percent. Vessel wall density also improved with treatment."

Link: http://www.eurekalert.org/pub_releases/2012-09/s-ftf092412.php

So let me start out here by noting that (a) I am eternally unsatisfied with the present, (b) Fight Aging! has been more or less static in traffic, scope, and focus for at least five years, and (c) past changes have come slowly, usually proceeded by a few years of rumbling. Time waits for no man, however, and it is ever the case that the modest efforts I make here could be better, could achieve more, and could consume more of my time than they do.

So without any particular ordering or desire to see anything happen immediately, here are some possible future directions.

Dumb it Down

Fight Aging! is heavy on the raw, undigested science these days: links to papers, quoted research abstracts. Unsurprisingly, there isn't much of a market for that sort of thing falling into your in-box - most people still run the other way when presented with scientific publications. In a way its been something of a surprise to see that the continued level of traffic that does wander past the front door and subscribe to the newsletter.

One time-worn approach to reaching a wider audience is to dumb things down (the uncharitable viewpoint) or replace the raw output of the scientific method with interpretation and explanation (the charitable viewpoint). In the context of Fight Aging!, this would mean posting fewer straight links to papers and quotes from those papers, replacing all of that with short articles that provide analysis and commentary on research - an emphasis on explanations of relevance and place in the growing foundations of tomorrow's biotechnology and medical science.

This would necessarily mean a slower pace of posting; perhaps once-a-day or thrice-a-week sort of schedule. Time is ever at a premium, and the time taken to write and think is time not taken to wade through papers, news, and blogs to discover new and interesting trinkets.

This might wind up more valuable, or it might wind up less valuable. Traffic generally falls off when you slow down, but traffic is an extremely poor measure of engagement or persuasion - in fact, pretty much everything you can measure is a poor representation of engagement or persuasion. I have my doubts that even actual revenue in for-profit businesses is a good proxy for these things.

Take the Advertising / Social Network / Traffic-Growing Path

There is a fairly standard playbook for growing traffic to a web site or subscriptions to a newsletter. At a very basic level it involves selling ads and then plowing that revenue into advertising for new traffic and new subscribers. If you manage it very well and you have something that people want to read, it's possible to grow at breakeven or a manageable cost that might later be recouped by cutting back on the spending.

Involving social networks in this model offers some additional options to replace the use of money with the use of time and cleverness, but follows much the same path: you are running a growth engine that tries to pull in people at one end and uses the fact that they passed through in order to convince more people to try it out.

You might look at Next Big Future or Singularity Hub as examples. Both sites touch on longevity science here and there and have prospered through this sort of mechanism.

But note my comments above on engagement and persuasion. Insofar as I care about anything that results from a visitor's time at Fight Aging!, I am interesting in convincing people to donate to SENS, to buy into engineered longevity as a goal, and then to convince their friends. These things are all exceedingly hard to measure, but if plunging into the traffic-growth business, one has to start by taking it on faith that increased traffic will lead to more of whatever it is you want people to take away from your site.

The flip side here is that you also have to take it on faith that the significant changes made to a site that are necessary in order to take the advertising / social network traffic growth path will not impact the message. The reasons why I have never taken that path in the past relate to this. For example, I'm sure you can imagine the sort of advertisers that would want to have their products touted here; any sort of easily managed integration with an advertising network would produce a deluge of "anti-aging" lies and nonsense. It's impossible to filter those things in a reasonable amount of time, and I'd end up looking just like every other opportunist with a web site.

In a market where fraud is so loud, well funded, and well entrenched that its proponents cause problems for the legitimate research and development community, it requires a significant investment in time (at a minimum) to proceed without being tainted.

Lastly, it should be noted that generating advertising revenue is not a matter of just sticking ads on a site and continuing as you were. You have to chase the most valuable forms of advertising, which means that the content must adapt itself to the advertiser if you wish to have any meaningful success. That again is great way to lose your way as a voice or a viewpoint or a set of goals.

The fundamental challenge here is that there are next to no ethical products and services relating to human longevity. I could probably rattle off a few: calorie restriction self-help materials, exercise gear, medical tourism resources, books from the small number of more reputable authors, and so forth. But I'd be hard pressed to name many more than a dozen categories here. This is an industry still well in its money sink phase: life science research and fundraising is the only meaningful game in town.

Change the Core Message

The core message of Fight Aging!, the one page I want everyone to read, is broadly educational in nature. It is, perhaps naively, intended as a thin bridge across the gaping chasm that lies between (a) someone who knows next to nothing of longevity science, but is vaguely interested in health and longevity, and (b) someone who knows enough to be interested in and a potential supporter of the Strategies for Engineered Negligible Senescence.

A range of assumptions are baked into this, such as the idea that it is a process to get from point (a) to point (b), and that this is an important pathway for people to follow today. Implicit in that are some opinions on where SENS supporters come from in terms of their journey through health matters and an awareness of scientific research - see the community diagram for example, which seems still moderately relevant some eight years later. I may or may not be right about any of this. I might have been right back in 2001, but things may be sufficiently different now that a new approach would be better.

Regardless, insofar as I'm selling SENS, it's a soft and gradual sell. I'm convinced that, at this time and for the next few years at the very least, delivering money to the SENS Foundation and its aura of allied research groups is the best thing we could all be doing for our future wellbeing. Significant extension of our healthy lives will only come from ways to rejuvenate the old and prevent aging - and no-one else is credibly working on that yet. I haven't made a habit of pushing that message until people revolt from the mere mention of it, however. From an intellectual perspective, I'd rather folk came to the same position as I have on their own, given the data and background to think on it.

There is a debate that might be had here on the value of direct and more forceful persuasion versus building the environment within which a much smaller number of people convince themselves - but it's a long one, so I'll pass it over for now.

Nonetheless, Fight Aging! could be reworked as a much harder sell: a fundraising site that also delivers relevant news as opposed to a news and interest site that happens to tout SENS as a charitable cause. This is actually more of a radical change than it might sound when stated that way.

Write a Book

There is certainly enough material here to digest into a book, and then rework the site to focus on it, but books age poorly. A book and its launch is something like a party: something you do once, bask in the glow for fifteen minutes or so, and then move on with life. If you're not drawing much attention with your ongoing writing, then a book is unlikely to change that state of affairs. Good reasons to write a book are (a) because you can't not write it, and (b) you have gathered a lot of attention already and would like to capitalize on that.

So as I see it, writing a book in order to generate more attention in the long term is getting things exactly backwards. About the only argument with merit that I can see for digesting a book from Fight Aging! is to better organize the entire, broader message presented here - but other books, more successful than I could ever reasonably expect to be, already do this, have done this over the past decade, and continue to emerge to do this on an ongoing basis.

Offer Consulting Services

It might be naive, but one has to imagine that by this time everything I've learned and considered on the topic of longevity science might be worth something to someone - if it could be rendered into some sort of palatable form. If you close your eyes it might be possible to envisage a future Fight Aging! that looks like a strategic consultancy, offering white papers and presentations to the corporate risk assessment world, or some other hypothetical customer that doesn't already know all I that I understand about this one facet of technological progress.

This is a venerable market, but the question is whether or not taking this direction - even if successful, which is a big if - helps the bottom line more than what I'm doing now, or more than any of these other hypothetical paths forward. That bottom line of course comes back to engagement, persuasion, and funds raised for SENS.

In Summary

Do I know where I'm going with this? Hell no, and any of the smart long-time readers could do just as well with a course of suggestions, I'm sure. But life is change: you don't change, you don't do better, and I think that Fight Aging! is well past the point at which something should be tried.

Via CNBC: "Google's Venture fund is planning to invest $1 billion in a wide-range of start-ups over the next five years, but the firm isn't necessarily looking for the next Facebook, Twitter or other media related business. ... 'There's a whole world of innovation out there outside of social media. It's a huge growth area, but we're investing a lot of money in life sciences,' said William Maris, Google Ventures managing partner. ... Maris said the fund seeks entrepreneurs that 'have a healthy disregard for the impossible' with forward-thinking ideas, especially in biotech. Maris said some of the areas he is interested in include businesses that are focused on radical life extension, cryogenics and nanotechnology. ... 'Part of my job is to discern the fine line between crazy and genius,' Maris said. 'We're looking for entrepreneurs that want to change the world for the better and that's important. So I do think our values are a little bit different than the typical sort of venture capitalist you might meet.'" This is just a comment, of course, and at present the fund isn't invested in anything that works directly towards the defeat of aging: one partner's views don't necessarily have anything to do with how the fund moves in aggregate. One of the real challenges in longevity science today is that there's little to effectively commercialize, even if you want to be really aggressive and pull results right out of research into an unregulated region of the world for development as a therapy. Things don't get interesting until SENS programs or similar start to deliver results that can be turned into an early product, or the tissue engineers and stem cell researchers make more of an inroad into reversing the changes in stem cell populations that occur with age. The leading edge of all this is still a few years away at the very earliest, and more like at least a decade for much of it, so far as I can see.

Link: http://www.cnbc.com/id/49105571

Author David Ewing Duncan is presently touting a new book on aging and aging research entitled "When I'm 164". Here is an audio interview: "With a new understanding of the biology of aging, we may be on the cusp of pushing life expectancy to ages once considered unimaginable. Journalist and author David Ewing Duncan in his book When I'm 164, examines the potential technologies that could lead us to radical life extension and some of the consequences should science bring about a dramatic demographic shift. We spoke to Duncan about his book, how close we are to scientific advancements in the area, and why not everyone wants to live forever. ... While riffing on the Beatle's song 'When I'm 64,' the book surveys the increasingly legitimate science of radical life extension - from Healthy Living and Genetics to Regeneration and Machine Solutions - and considers the pluses and minuses of living to age 164, or beyond; everything from the impact on population and the cost of living to what happens to love, curiosity, and health. He shares classic stories and myths of people determined to defeat aging and death, and offers real-life tales of the techno-heroes and optimists who believe that technology can solve the 'problem' of aging. Concluding that anti-aging technologies will probably succeed in the next 30-50 years despite his earlier skepticism, he brings us back to the age-old question: 'will you still need me, will you still feed me, when I'm...'"

Link: http://www.burrillreport.com/article-will_biotech_double_life_expectancy.html

Something to think about for today: SENS, the Strategies for Engineered Negligible Senescence is not put forward as a theory of aging, but it is a theory of aging, one that pulls from many other partial attempts to explain aging. It purports to describe, as best we know, the detailed mechanisms that lie at the root of degenerative aging - but is presented (and currently running) as a program of research and development to reverse aging. That is the testable part of the theory, if you like: implement SENS and we should see rejuvenation. If this comes to pass, then it is true that SENS as laid out at present does describe all forms of fundamental damage that cause aging. If not, then SENS is either wrong or, more likely, incomplete - there is some other form of damage that is important and unconnected to those already discovered.

(No new form of fundamental change or damage related to aging has been identified in the past 25 years, across a time of raging progress in biotechnology, which should gives us some confidence that there are no others. There is always room to argue, however, and science is anything but static).

There are, it has to be said, a great many theories of aging. Following this line of thinking, it occurs to me that we can classify most theories of aging according to where they stand with respect to the hole we find ourselves in - that hole being the inconvenient fact that we're all aging to death, and progressively increasing suffering and pain lies in each of our personal futures.

I see three broad buckets for this hole-based taxonomy:

• How did we get into this hole?
• What is going on in here?
• How do we get out of this hole?

How did we get into this hole?

Evolutionary theories of aging seek to explain how we came to age the way we do. Here the proposed mechanisms of aging inform the discussion and modeling of plausible evolutionary processes that would produce them - as well as the staggering variety in lifespan and pace of aging that exists in the natural world. I see this as scientific dispassion at its finest: "Look at the interesting way in which we're all dying! Fascinating, no? We should take some time to think about how this came to pass."

What is going on in here?

Other theories of aging focus on modeling how aging happens: what are the exact mechanisms? Many different approaches to these theories exist. Consider, for example, those that describe aging at the high level, such as in the use of reliability theory to frame aging in the form of a systems failure model. At the other end of the room we have things like the mitochondrial free radical theory of aging, which proposes detailed and particular mechanisms in cells and cellular components that lead to damage and then the larger-scale manifestations of aging.

How do we get out of this hole?

So here we return to SENS, a meta-theory of aging that pulls from many of the mechanism-focused theories of aging proposed over the past century. Until the advent of SENS there really wasn't any sort of contingent in the scientific community whose members presented a theory of aging as something more like a theory on how to defeat aging - to prevent and treat aging with therapies, reverse frailty in the old by removing its root causes, and stop the young from becoming aged.

So we are in a hole, no arguing that. Getting out does require some understanding of the hole in order to best direct efforts - but the scientific community is far and away past the point at which we could be effectively working our way out. Spending all our time gathering more knowledge is no longer good strategy. We in fact don't need to know all that much about how we got here, nor exactly how fundamental causes of aging spiral outward to create the thousand and one causes of death we observe in old people. What SENS tells us is that we just need to know what those root causes are and how to fix them. Additional information is useful, and will probably improve efficiency, but it is not absolutely necessary and nowhere near as important as just forging ahead to get the job done. The test of SENS as a theory aging is for the research community to get out there and actually fix the problems that are killing us.

Some interesting results from genetic research: scientists "have shown definitively that a small number of places in the human genome are associated with a large number and variety of diseases. In particular, several diseases of aging are associated with a locus which is more famous for its role in preventing cancer. For this analysis, [researchers] cataloged results from several hundred human Genome-Wide Association Studies (GWAS) from the National Human Genome Research Institute. These results provided an unbiased means to determine if varied different diseases mapped to common 'hotspot' regions of the human genome. This analysis showed that two different genomic locations are associated with two major subcategories of human disease. ... More than 90 percent of the genome lacked any disease loci. Surprisingly, however, lots of diseases mapped to two specific loci, which soared above all of the others in terms of multi-disease risk. The first locus at chromosome 6p21, is where the major histocompatibility (MHC) locus resides. The MHC is critical for tissue typing for organ and bone marrow transplantation, and was known to be an important disease risk locus before genome-wide studies were available. Genes at this locus determine susceptibility to a wide variety of autoimmune diseases ... The second place where disease associations clustered is the INK4/ARF (or CDKN2a) tumor suppressor locus [also known as p16]. This area, in particular, was the location for diseases associated with aging: atherosclerosis, heart attacks, stroke, Type II diabetes, glaucoma and various cancers. ... The finding that INK4/ARF is associated with lots of cancer, and MHC is associated with lots of diseases of immunity is not surprising - these associations were known. What is surprising is the diversity of diseases mapping to just two small places: 30 percent of all tested human diseases mapped to one of these two places. This means that genotypes at these loci determine a substantial fraction of a person's resistance or susceptibility to multiple independent diseases. ... In addition to the MHC and INK4/ARF loci, five less significant hotspot loci were also identified. Of the seven total hotspot loci, however, all contained genes associated with either immunity or cellular senescence. Cellular senescence is a permanent form of cellular growth arrest, and it is an important means whereby normal cells are prevented from becoming cancerous. It has been long known that senescent cells accumulate with aging, and may cause aspects of aging. This new analysis provides evidence that genetic differences in an individual's ability to regulate the immune response and activate cellular senescence determine their susceptibility to many seemingly disparate diseases."

Link: http://news.unchealthcare.org/news/2012/september/diseases-of-aging-map-to-a-few-hotspots-on-the-human-genome

A comprehensive understanding of the brain is an important line item for future medical development, as the research community will have to develop ways to repair the brain and reverse aspects of its aging while preserving the structures that encode the mind. Here is a look at one of the higher profile projects of recent years: "Paul Allen, the 59-year-old Microsoft cofounder [has] plowed $500 million into the Allen Institute for Brain Science, a medical Manhattan Project that he hopes will dwarf his contribution as one of the founding fathers of software. The institute, scattered through three buildings in Seattle's hip Fremont neighborhood, is primarily focused on creating tools, such as the mouse laser, which is technically a new type of microscope, that will allow scientists to understand how the soft, fleshy matter inside the human skull can give rise to the wondrous, mysterious creative power of the human mind. ... His first $100 million investment in the Allen Institute resulted in a gigantic computer map of how genes work in the brains of mice, a tool that other scientists have used to pinpoint genes that may play a role in multiple sclerosis, memory and eating disorders in people. Another $100 million went to creating a similar map of the human brain, already resulting in new theories about how the brain works, as well as maps of the developing mouse brain and mouse spinal cord. These have become essential tools for neuroscientists everywhere. Now Allen, the 20th-richest man in America, with an estimated net worth of $15 billion, has committed another $300 million for projects that will make his institute more than just a maker of tools for other scientists, hiring several of the top minds in neuroscience to spearhead them. One effort will try to understand the mouse visual cortex as a way to understand how nerve cells work in brains in general. Other projects aim to isolate all the kinds of cells in the brain and use stem cells to learn how they develop. Scientists think there may be 1,000 of these basic building blocks, but they don't even know that. 'In software,' Allen says, 'we call it reverse engineering.'"

Link: http://www.forbes.com/sites/matthewherper/2012/09/18/inside-paul-allens-quest-to-reverse-engineer-the-brain/

A few days back, I pointed out research that indicates brain cells increasingly become senescent with age. This is a challenge: we want to get rid of senescent cells and prevent their buildup because the harm they cause contributes to degenerative aging, but the obvious way to do that is through targeted destruction via one of the many types of cell-targeting and cell-killing technologies presently under development. This is fine and well for tissues like skin and muscle, in which cells turn over and are replaced - but in the brain and nervous system there are many small but vital populations of cells that are never replaced across the normal human life span. The cells you are born with last a lifetime, and some fraction of those cells contain the data that makes up the mind.

Thus it begins to seem likely that we can't just rampage through and destroy everything that looks like a senescent cell: possible therapies to address cell senescence as a contribution to aging will have to be more discriminating, and so more complex and costly to develop.

Following on in this topic, I noticed an open access paper today that examines the role of cellular senescence of astrocyte, the support cells of the brain, in Alzheimer's disease (AD). Unlike the research I noted above, the biochemical signatures of senescence examined here are the same as those used in last year's mouse study showing benefits resulting from a (necessarily) convoluted way of destroying senescent cells as they emerge - which of course starts the mind wandering on what might be going on in the brain of these mice. Astrocytes can perhaps be replaced without harming the mind or important nervous cells, but what about other cells in the brain?

In any case, here is the paper:

Astrocyte Senescence as a Component of Alzheimer's Disease

A recent development in the basic biology of aging, with possible implications for AD, is the recognition that senescent cells accumulate in vivo. Although senescent cells increase with age in several tissues, little is known about the potential appearance of senescent cells in the brain. The senescence process is an irreversible growth arrest that can be triggered by various events including telomere dysfunction, DNA damage, oxidative stress, and oncogene activation. Although it was once thought that senescent cells simply lack function, it is now known that senescent cells are functionally altered. They secrete cytokines and proteases that profoundly affect neighboring cells, and may contribute to age-related declines in organ function.

...

Astrocytes comprise a highly abundant population of glial cells, the function of which is critical for the support of neuronal homeostasis. ... Impairment of these functions through any disturbance in astrocyte integrity is likely to impact multiple aspects of brain physiology. Interestingly, astrocytes undergo a functional decline with age in vivo that parallels functional declines in vitro. We demonstrated that in response to oxidative stress and exhaustive replication, human astrocytes activate a senescence program.

...

The importance of senescent astrocytes in age-related dementia has been the subject of recent discussion, but to date, there is little evidence to suggest that senescent astrocytes accumulate in the brain. In this study, we examined brain tissue from aged individuals and patients with AD to determine whether senescent astrocytes are present in these individuals. Our results demonstrate that senescent astrocytes accumulate in aged brain, and further, in brain from patients with AD.

Furthermore, since Aβ peptides induce mitochondrial dysfunction, oxidative stress, and alterations in the metabolic phenotype of astrocytes; we examined whether Aβ peptides initiate the senescence response in these cells. In vitro, we found that exposure of astrocytes to Aβ1-42 triggers senescence and that senescent astrocytes produce high quantities of interleukin-6 (IL-6), a cytokine known to be increased in the [central nervous system] of AD patients. Based on this evidence, we propose that accumulation of senescent astrocytes may be one age-related risk factor for sporadic AD.

As I mentioned in the last post on this subject, this all seems to point to the likely need for ways to reverse cellular senescence, not just selectively destroy senescent cells - at least for some populations of nerve cells. One open question here is whether fixing all the known fundamental forms of cellular damage (as described in the Strategies for Engineered Negligible Senescence) would be sufficient to achieve this end.

A nice demonstration of the degree to which the pace of aging is inherited - but remember that for the vast majority of us, lifestyle choices have more influence than genes, while progress in medical technology trumps all such concerns: "Various measures incorporated in geriatric assessment have found their way into frailty indices (FIs), which have been used as indicators of survival/mortality and longevity. Our goal is to understand the genetic basis of healthy aging to enhance its evidence base and utility. We constructed a FI as a quantitative measure of healthy aging and examined its characteristics and potential for genetic analyses. Two groups were selected from two separate studies. One group (OLLP for offspring of long-lived parents) consisted of unrelated participants at least one of whose parents was age 90 or older, and the other group of unrelated participants (OSLP for offspring of short-lived parents), both of whose parents died before age 76. FI(34) scores were computed from 34 common health variables and compared between the two groups. The FI(34) was better correlated than chronological age with mortality. The mean FI(34) value of the OSLP was 31% higher than that of the OLLP. The FI(34) increased exponentially, at an instantaneous rate that accelerated 2.0% annually in the OLLP and 2.7 % in the OSLP consequently yielding a 63% larger accumulation in the latter group. The results suggest that accumulation of health deficiencies over the life course is not the same in the two groups, likely due to inheritance related to parental longevity. Consistent with this, [sibling pairs] were significantly correlated regarding FI(34) scores, and heritability of the FI(34) was estimated to be 0.39. ... Variation in the FI(34) is, in part, due to genetic variation; thus, the FI(34) can be a phenotypic measure suitable for genetic analyses of healthy aging."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22986583

An open access review paper that looks at the use of fruit flies in studying the details of immune system aging: "Aging is a complex process that involves the accumulation of deleterious changes resulting in overall decline in several vital functions, leading to the progressive deterioration in physiological condition of the organism and eventually causing disease and death. The immune system is the most important host-defense mechanism in humans and is also highly conserved in insects. Extensive research in vertebrates has concluded that aging of the immune function results in increased susceptibility to infectious disease and chronic inflammation. Over the years, interest has grown in studying the molecular interaction between aging and the immune response to pathogenic infections. The fruit fly Drosophila melanogaster is an excellent model system for dissecting the genetic and genomic basis of important biological processes, such as aging and the innate immune system, and deciphering parallel mechanisms in vertebrate animals. Here, we review the recent advances in the identification of key players modulating the relationship between molecular aging networks and immune signal transduction pathways in the fly. Understanding the details of the molecular events involved in aging and immune system regulation will potentially lead to the development of strategies for decreasing the impact of age-related diseases, thus improving human health and life span."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3431831/

You'll find some thoughts on research into aging and longevity at In Search of Enlightenment:

Yesterday I attended this interesting talk on the 5 year priorities and vision of Canada's Institute of Aging. Many interesting issues arose in the talk and the discussion that followed that illustrate the ongoing challenges which the field of biogerontology faces.

...

For a population to approach a life expectancy near 100 years we would have to eliminate most cancers, heart disease and stroke. Considering we have not yet eliminated any one of these diseases, the suggestion that we will continue to increase life expectancy at the same rate as we have in the past is simply unfounded. Take mice in the laboratory. On average, they could life about 2 years if they are fed, protected from predators, etc. Can we get them to live significantly longer by trying to treat all the diseases that afflict them in late life? No. ... We should invest more research dollars into the biology of aging than we do into any one specific disease of aging (e.g. cancer, heart disease, etc.). Unfortunately my sense is that we don't come even close to this. Biogerontology continues to be disadvantaged as a field of scientific inquiry.

...

My sense of things, from hearing about the vision of the Institute and the new priorities it has identified, is that the Institute of Aging in Canada still struggles to get the respect, funding and support it deserves. This is no doubt due to many factors, such as the dominance of disease research, misconceptions about the true causes of health disparities, misguided sensibilities of fairness, ageist attitudes, and a general ignorance of the biology of aging and evolutionary biology in general. This makes selling the science to politicians and the general public a really tough sell. But I believe it is something that must be done if we hope to add healthy years to late life. So we must soldier on....

This is all quite true. People are surprisingly willing to write off and accept suffering and death in the old - see the various forms of "fair innings" arguments used to divert funds away from medical programs for the elderly, for example. At the same time, the research and clinical medicine systems in the most advanced regions of the world are a horrid centralized mess, in which most of the important actors operate under perverse regulatory incentives that encourage them to provide worse service, build poor products, and devote the lion's share of scientific resources to the least effective research programs.

In the US, this manifests most noticeably in the way in which the FDA forbids any application of science to treat aging - all medicine must treat a specific, defined, named disease, and there is no place or path forward within the existing framework to add aging to the list. This is characteristic of the late stage of regulation that has become so stifling as to completely block meaningful progress - all that is not expressly allowed is forbidden by default. This is exactly why there are not a hundred biotech startups working on technologies like those proposed in the Strategies for Engineered Negligible Senescence, many of which within a few years of the point at which it makes sense to build a product. But there is no realistic path to commercial deployment of a therapy for aging in the largest markets, so there is next to no venture funding for these goals.

What little research does happen takes place in parts of the field that will never produce meaningful rejuvenation biotechnologies, but which can be shoehorned into the existing regulatory straightjacket because they sort of look like drug development and can be tested on lifestyle diseases like diabetes. Billions have been spent on such ends already, an example of the way in which regulation produces massive waste by constraining the engines of competition and progress to research and build only shoddy incremental advances on yesterday's known goods. But that is not where true progress comes from - true progress comes from disruptive new advances that look nothing like the technology of yesteryear.

For so long as the US regulation of research, medical development, and clinical provision of services looks much as it does today, the future of rejuvenation biotechnologies lies in medical tourism to other parts of the world. Research and development once conducted here will be overtaken by that in parts of the world that do not forbid attempts to produce therapies to reverse aging. But it will take longer for all of this to take off and become an earnest, large development community than if there were no ball and chain attached to medical research in the US - and every day of delay bears an enormous cost in death and suffering.

Examination of the sweeping low-level changes in biochemistry brought on by calorie restriction continues apace: "Calorie restriction (CR) promotes longevity. A prevalent mechanistic hypothesis explaining this CR effect suggests that protein degradation, including mitochondrial autophagy, is increased, thereby removing damaged proteins. At steady state, increased catabolism must be balanced by increasing mitochondrial biogenesis and protein synthesis, resulting in faster protein replacement rates. To test this hypothesis, we measured replacement kinetics and concentrations of hundreds of proteins in vivo in long-term CR and ad libitum -fed mice ... CR reduced absolute synthesis and breakdown rates of almost all measured hepatic proteins and prolonged half-lives of most (~80%), particularly mitochondrial proteins ... Proteins with related functions exhibited coordinated changes in concentration as well as replacement rates. ... In summary, our combination of dynamic and quantitative proteomics suggest that long-term CR reduces mitochondrial biogenesis and mitophagy are reduced. Our findings contradict the theory that CR increases mitochondrial protein turnover, and provide compelling evidence that cellular fitness is accompanied by reduced global protein synthetic burden."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22984287

This author defines aging as "an age-dependent trajectory of interacting system states - the sum of all molecular and physiological states and their interaction networks, many but not all of which shift in a consistent direction over time. This definition broadens our focus to include components that do not themselves depend on age, but which cohabit networks containing components that do. Gene-environment interactions are a case in point, wherein environmental variation can help to shape the age-structure of a population despite being quite obviously independent of age. Perhaps the best-established genetic pathway to influence lifespan is insulin-like signaling, believed to have evolved at least in part for its ability to maximize reproduction under favorable environments while postponing both reproduction and individual mortality under conditions of crowding or insufficient food ... Since natural populations are polymorphic for ostensibly rate-limiting components of this pathway, it is likely that individuals genetically predisposed to low insulin-like signaling should survive famine better than those geared for higher signaling and shorter lifespan. This is a conclusion of some import for population biologists, since the age-composition of any population must then be modified by the availability of food. A particularly instructive example is the near-ubiquitous evolutionary requirement for species or their constituent populations to survive extended periods of famine. Groups experiencing more prolonged famines (or just over-wintering, if their lifespans are measured in weeks) will have more diverse age structures, including an increased number of individuals for whom reproduction has been delayed. ... The same potential also exists for gene-gene interactions (including genes that dictate dietary preferences) to affect long-term survival. For example, only one component of a gene network may actually be age-dependent, while other genes create the background context of homeostatic states and their oscillations within which age-dependent genes must function. An increased probability of death with age could then arise from components undergoing essentially monotonic age-dependent declines, confronting extreme-value system states (in variable but age-independent parameters) to which they cannot respond adequately in any essential tissue or organ. Alternatively, an age-dependent increase in the variance of system oscillations may exceed the response range of one or more age-independent gene functions. In either case, the precise cause of death or debility will vary in a stochastic way, appearing as the 'weakest link' in any one tissue or organism, although the underlying age-associated changes may be common to many or all cell types and individuals."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427912/

Today I'll point out an open access book manuscript on the biodemography of longevity, entitled Between Zeus and the Salmon; this is a goodly amount of reading material, and will probably keep you busy for a weekend or two. It's written from the conservative mainstream point of view, which is to say that it expresses the assumptions that (a) any future change in human longevity will be incremental and small, because (b) no radical advances in biotechnology applicable to aging are waiting in the wings, and (c) manipulation of longevity-related genes to slow aging is the best way forward, even though it will be slow, hard, challenging work. This is wrong, wrong, wrong - but that's always the way of the mainstream. They are there to be surprised and disrupted by suddenly rushing technological advancement, discontinuities in the pace of progress that occur increasingly frequently in this age of ours.

If you want to understand this mainstream of longevity research and its viewpoints on present day and near future challenges in the field, however, then this is a great resource:

As I see it, for demographers today, the golden challenge is to make the right judgment call predicting our children's life spans. Will the recent pace of gains in life expectancy and active life expectancy extend to the next generation, or are we approaching the point of diminishing returns? The deep theoretical questions in the demography of mortality and aging - including the proper framework for incorporating genetic variables and cofactors into demographic models - cluster around this very practical question of prediction, whose answer some of us may live to know.

Confronting this question, the in-house tools of traditional demography - accurate accounting of vital trends and descriptive modeling of variability across time and circumstances - are indispensable but inconclusive. Knowledge of detailed mechanisms is too patchy for causal models with aggregate implications. Thus demographers are thrown back on a search for analogues. Biology is our cornucopia of analogues.

I do not want to overstate the relevance of biology to demography. Biology will not settle demographic questions directly. Finding the causes behind the leveling out of fruit-fly hazard functions after 100 days will not disclose the causes behind any leveling out of human hazard functions after 100 years. Genes promoting survival at advanced ages may be found in nematode worms without giving us any right to expect usefully close counterparts in people. Darwinian theory, for all its triumphs, is a poor basis for predicting whether women's advantage in life expectancy over men will be increasing or decreasing in 2047.

Nonetheless, biology is definitive. Experiments with laboratory organisms, genetic mapping, natural history, and evolutionary theory are defining the intellectual landscape within which demographic arguments and forecasts gain or lose their appeal. Uncertainties are so great and mortality prediction is so much a matter of bets and guesses that the powerful analogies provided by biology are the best guides we have.

But we now enter an age in which biology is increasingly ours to command - and by extension we will soon enough no longer be limited by the outcome of past evolution. By 2047, asking after the degree to which women outlive men will be something akin to asking today whether Englishmen or Frenchmen better resist scurvy. It's a question that has no relevance, buried completely by the advance of medicine and medical knowledge: by 2047, our ability to extend the human life span will dwarf any natural difference due to gender.

Nonetheless, you'll find some interesting material here on many varied topics, such as ongoing research into the genetics of human longevity:

Central to my own thinking are a pair of questions that I call the "hundreds-thousands-tens-of-thousands" questions. The first question is this: How many genes should I imagine there being whose specific effects on old-age survival are strong enough to be noticeable in a population? The second question is the converse: How many genes should I imagine typically having to act in concert to produce any one noticeable effect on old-age survival in a population?

I used to think that the answers to these questions were likely to be at the tens-of-thousands end of the scale of orders of magnitude and that the biodemography of longevity would have to become a sort of statistical mechanics before it could make sense. But I have been strongly impressed by the life of Madame Calment and the data on survival at extreme age ... Humans who make it to 110 years of age appear to have truly better further survival rates than those who make it to 95 or 100. No obvious behavioral and environmental determinants of extreme survival have turned up as yet. It therefore seems as if there could be a relatively small number of bad genes - hundreds, not tens-of-thousands - which one has to not have in order to survive ad extrema.

The topic of late life plateaus in mortality crop ups again here - that mortality rates stop advancing at some point very late in life, and stay high but static. This seems to be an idea that has gathered more attention from the broader research community over recent years. Certainly the evidence for this phenomenon in flies is iron-clad, but there is skepticism and debate over what sort of interpretation is supported by the far more limited human data.

The members of a number of mammal species, ourselves included, live long past their reproductive years. The question would be why this postreproductive longevity has evolved: what advantage does it confer? For humans, the grandmother hypothesis suggests that it has something to do with enhancing the survival of grandchildren, but this is debated. Here, researchers look at killer whales to argue that the advantage lies in enhanced survival of the male children of long-lived mothers: "Prolonged life after reproduction is difficult to explain evolutionarily unless it arises as a physiological side effect of increased longevity or it benefits related individuals (i.e., increases inclusive fitness). There is little evidence that postreproductive life spans are adaptive in nonhuman animals. By using multigenerational records for two killer whale (Orcinus orca) populations in which females can live for decades after their final parturition, we show that postreproductive mothers increase the survival of offspring, particularly their older male offspring. This finding may explain why female killer whales have evolved the longest postreproductive life span of all nonhuman animals." Male mammals are capable of siring offspring far later in life than females, so if a longer-lived mother can increase the number of years in which a male child continues to mate, that would constitute an advantage even if the mother can no longer reproduce.

Link: http://www.ncbi.nlm.nih.gov/pubmed/22984064

An open access paper: "'Man is as old as his arteries.' This old aphorism has been widely confirmed by epidemiological and observational studies establishing that cardiovascular diseases can be age-related in terms of their onset and progression. Besides, with aging come a number of physiological and morphological changes that alters cardiovascular function and lead to subsequently increased risk of cardiovascular disease, even in health asymptomatic individuals. Even though different adaptive mechanisms to protect blood vessels against mild stress have been described, the aging process induces a progressive failure of protective mechanisms, leading to vascular changes. The outcomes of the aging-related modifications are the impairment of homeostasis of the irrigated organs and resultant target organ damage. The increasing mean age of the population in industrialized countries has turned out to be an economic and public health problem, as the increase in life expectancy goes in parallel with high incidence of several pathological conditions, despite unprecedented advances in prevention, diagnostics, and treatment. Of all aging-related illness, cardiovascular diseases remain the leading cause of morbidity and mortality in the elderly, and thus it is imperative to understand the mechanism underlying cardiovascular senescence."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3429093/

Plastination is the basis for a possible technology platform that might compete with the low-temperature vitrification used in cryonics. In both cases the goal is to preserve the mind after death by preserving the fine structure of brain tissue - in which the data of the brain is encoded. This is the only chance at a longer life in the future available to those folk who will age to death because they are presently too old to wait out the near future of rejuvenation biotechnology.

Cryopreservation requires ongoing low-temperature storage whereas plastination does not. Both involve infusing tissues with chemicals, meaning that future restoration will require advanced technology - such as directed swarms of molecular machines that can repair each individual cell, remove all of the chemicals used in preservation, and so forth. The details would vary greatly depending on which preservation method was used, of course. But preserved individuals have time to wait for future progress in technology, and molecular nanotechnology of this sort is well understood to be possible and plausible.

It should be noted that there is a contingent of futurists who believe any copy of the self to be a valid continuation of the self, and who seek to preserve themselves via cryonics in the belief that they will be copied to run as software emulations in the future - the original preserved tissue to be discarded after that use. This will probably be easier to accomplish than physical restoration of the original, but from my perspective a copy of you is not you. I adhere to the definition of the self as the continuation of this slowly changing structure that is me, the changing pattern encoded in this particular set of matter. Given that copying will probably be easier than restoration, it is worth thinking about going into cryopreservation with an attached note (or tattoo or embedded metal plate) to say "do not copy, restore the original" if you have strong feelings about identity as continuity rather than simply a pattern.

In any case, I thought I'd point out a couple of articles on plastination from recent days:

How to Live Forever By Turning Your Brain Into Plastic

Assuming that brain plastination eventually comes into practice, the first step, regrettably, is that you have to die.

This could be in or near a hospital, hospice, or your home. Moments after your death, a response team will start the process of emergency glutaraldehyde perfusion (EGP) for protein fixation (a kind of advanced embalming process). This has to happen within 15 minutes of your death, otherwise the first phase of neural degradation will start to set in; brain cells start to die on account of oxygen deprivation.

The infusion of this molecule by the response team basically freezes your brain into place, creating a snapshot of your identity and your long term memories - though you might lose some short-term memories when you resume life after reanimation, just as sometimes happens after brain trauma today. "Glutaraldehyde is a very small chemical that gets into all your cells, and locks down your proteins and cytoskeleton, creating a kind of molecular cage," said Smart, "all protein-related interactions grind to a halt because of this crosslinking."

After this, your body will be moved to a centralized facility where, over the course of several months, your brain will be carefully removed and placed into a bath. Unlike cryonics, this stage is not time sensitive (whereas the standard saying at cryonics facilities is "time is trauma"). It's at this point that a chemical called osmium tetroxide fixes all the fats and fluid membranes in the brain cells. Then, a series of acetone-like solvents are used to convert the brain into plastic where it can be stored at room temperature. "All the water gets leached, out, but all the protein (and presumably, the other critical features) is still there," says Smart, "and so are all the neural connections, as are all the neural weightings - including the three dimensional structure."

Chemical brain preservation: how to live 'forever' - a personal view

A number of neuroscientists, working today with simple model organisms, are investigating the hypothesis that chemical brain preservation may inexpensively preserve the organism's memories and mental states after death. Chemically preserved brains can be stored at room temperature in cemeteries, contract storage, even private homes.

Our 501c3 nonprofit organization, the Brain Preservation Foundation, is offering a $100,000 prize to the first scientific team to demonstrate that the entire synaptic connectivity ("connectome") of mammalian brains can be perfectly preserved using either chemical preservation or more expensive cryopreservation techniques.

Such preserved brains may be "read" in the future, analogous to the way a computer hard drive is read today, so that either memories or the complete identities of the preserved individuals can be restored or "uploaded" in computer form.

As you might note, there is some thought that plastination might be cheaper than cryonics, but this may or may not pan out once total costs over time are figured in. Liquid nitrogen for temperature maintenance is very cheap and all the other costs of long term storage would be much the same once you remove that from the picture: rent, security, and so forth. Both processes require a skilled team up front at the time of death, and the initial portion of preservation is time critical - which is where the majority of the one-time costs appear, as it isn't cheap to keep a team on standby.

Progress towards ways to repair mitochondria is very important: a way to fix our age-damaged mitochondria is a necessary part of any toolbox of therapies capable of reversing aging. An upcoming conference provides some insight into the present state of research: "After the success of the two first editions held in 2010 & 2011, the Scientific Committee of the International Society of Antioxidants in Nutrition and Health (ISANH) decided to organize the 3rd World Congress on Targeting Mitochondria which will be held in Berlin in November 8-9, 2012. Mitochondrial dysfunctions are associated with hundred of pathologies such as cancer, diabetes, neurodegenerative diseases, migraine, infertility, kidney diseases, liver diseases, toxicity of HIV drugs, aging... It is becoming a necessity and an urge to know why and how to target mitochondria with bioactive molecules, drugs or nutrients in order to treat and prevent pathologies and chronic diseases. This 3rd World Congress on Targeting Mitochondria will cover a variety of new strategies and innovations as well as clinical applications in Mitochondrial Medicine. ... The Scientific Committee has selected two hot topics for this year's meeting. The first topic involves Mito-Devices, which are novel tools for probing mitochondrial function under physiological and pathological conditions. The second topic focuses on Mito-Engineering, i.e. novel strategies and means towards manipulations of mitochondrial function. Mito-devices and Mito-engineering are essential for making mitochondria-targeted therapeutics clinical feasible, therefore clinical applications are the underlying theme of the 3rd edition of Targeting Mitochondria."

Link: http://www.targeting-mitochondria.com

A popular science article on recent progress in organ engineering: "Implanting such a 'bioartificial' organ would be a first-of-its-kind procedure for the field of regenerative medicine, which for decades has been promising a future of ready-made replacement organs - livers, kidneys, even hearts - built in the laboratory. For the most part that future has remained a science-fiction fantasy. Now, however, researchers like Dr. Macchiarini are building organs with a different approach, using the body's cells and letting the body itself do most of the work. ... So far, only a few organs have been made and transplanted, and they are relatively simple, hollow ones - like bladders and [windpipes] ... But scientists around the world are using similar techniques with the goal of building more complex organs. At Wake Forest University in North Carolina, for example, where the bladders were developed, researchers are working on kidneys, livers and more. Labs in China and the Netherlands are among many working on blood vessels. The work of these new body builders is far different from the efforts that produced artificial hearts decades ago. Those devices, which are still used temporarily by some patients awaiting transplants, are sophisticated machines, but in the end they are only that: machines. Tissue engineers aim to produce something that is more human. They want to make organs with the cells, blood vessels and nerves to become a living, functioning part of the body. Some, like Dr. Macchiarini, want to go even further - to harness the body's repair mechanisms so that it can remake a damaged organ on its own."

Link: http://www.nytimes.com/2012/09/16/health/research/scientists-make-progress-in-tailor-made-organs.html?pagewanted=all

Senescent cells build up in our tissues with age. These cells have become damaged or passed the Hayflick limit and thus fallen out of the normal cell cycle of division. They should either self-destruct or be destroyed by the immune system, and until that happens they secrete all sorts of undesirable signaling compounds that tend to harm surrounding tissues. The more senescent cells you have, the more harm they cause - and the growth in their numbers with passing years is one of the root contributing causes of aging.

Given this outline, plans for dealing with the problem tend to involve identifying and destroying senescent cells - removing the cells from the picture is fairly clearly the way to go. The destroying part is pretty easy (there is no shortage of methods to kill cells) but the identification part is still a challenge, despite considerable progress from the cancer research community in building ways to target specific cell populations via aspects of their surface chemistry or other characteristics. At this point the state of the art demonstration of improved health in mice through destruction of senescent cells requires a combination approach of gene engineering and a targeted therapy, which isn't terribly practical as the basis for a human therapy.

Progress will be made nonetheless, and a near-future brace of therapies that remove the contribution of senescent cells to aging seems to be very plausible at this point. Yet this all assumes that senescent cells can be wiped out on an ongoing basis without consequence: a fair enough assumption for most tissues, made up of cells that are replaced and replenished on an ongoing basis. Recent research suggests, however, that cells that are far less readily replaced or are normally not replaced at all in the life span of an individual also turn senescent with age - such as those in the brain.

Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response:

In senescent cells, a DNA damage response drives not only irreversible loss of replicative capacity but also production and secretion of reactive oxygen species (ROS) and bioactive peptides including pro-inflammatory cytokines. This makes senescent cells a potential cause of tissue functional decline in aging.

To our knowledge, we show here for the first time evidence suggesting that DNA damage induces a senescence-like state in mature postmitotic neurons in vivo. About 40-80% of Purkinje neurons and 20-40% of cortical, hippocampal and peripheral neurons in the myenteric plexus from old [mice showed inceasing senescence-like characteristics] with age.

...

We conclude that a senescence-like phenotype is possibly not restricted to proliferation-competent cells. Rather, dysfunctional telomeres and/or accumulated DNA damage can induce a DNA damage response leading to a phenotype in postmitotic neurons that resembles cell senescence in multiple features. Senescence-like neurons might be a source of oxidative and inflammatory stress and a contributor to brain aging.

So if this research holds up we can't just rampage through the body and destroy everything that looks like a senescent cell. More discrimination is needed, which in turn means more complex therapies and a greater understanding of differences in biochemistry between the cell populations of interest. More to the point, we will also need some method of reversing this senescence-like state in the brain and nervous system cells that we want to keep around. Will a general repair of all of the known forms of cellular damage be sufficient for that? Is neural dysfunction absolutely a consequence of the damage modes described by the Strategies for Engineered Negligible Senescence? It seems unlikely that we'll get a solid answer to that question until SENS version 1.0 is implemented in mice, but the initial expectation would be that yes, it is.

And what about the mice that were treated with a method to destroy senescent cells? They didn't appear to have their brain function markedly impacted, or the researchers would have noted as much. However: (a) it was a study using mice engineered to age rapidly, and thus may not have lasted long enough to uncover issues of that sort, and (b) the method used to destroy senescent cells was very narrow and specific in its targeting, and may or may not have reached these neurons that fall into a senescence-like state.

SENS Foundation manages a program of research, development, and advocacy for rejuvenation biotechnology - building the foundation for therapies that will reverse aging in the old by repairing the cellular and biochemical damage that causes it. At present the Chase Community Giving event at Facebook is winding to a close on the 19th of this month, with $10,000 grants provided to those charities given the most votes by the community. So if you have a Facebook account, take a few moments to head on over to the SENS Foundation page and add your vote. Similar past events have demonstrated that there are more than enough SENS supporters out there to win any charitable popularity measure like this; so vote before the 19th and pass it on to your friends.

Link: https://www.facebook.com/ChaseCommunityGiving/app_162065369655?cv=2&app_data=location|/charity/view/ein/94-3473864

Researchers continue to make progress in induced nerve regeneration: "researchers were able to regenerate 'an astonishing degree' of axonal growth at the site of severe spinal cord injury in rats. Their research revealed that early stage neurons have the ability to survive and extend axons to form new, functional neuronal relays across an injury site in the adult central nervous system (CNS). The study also proved that at least some types of adult CNS axons can overcome a normally inhibitory growth environment to grow over long distances. Importantly, stem cells across species exhibit these properties. ... The scientists embedded neural stem cells in a matrix of fibrin [mixed] with growth factors to form a gel. The gel was then applied to the injury site in rats with completely severed spinal cords. ... Using this method, after six weeks, the number of axons emerging from the injury site exceeded by 200-fold what had ever been seen before. The axons also grew 10 times the length of axons in any previous study and, importantly, the regeneration of these axons resulted in significant functional improvement. ... The grafting procedure resulted in significant functional improvement: On a 21-point walking scale, without treatment, the rats score was only 1.5; following the stem cell therapy, it rose to 7 - a score reflecting the animals' ability to move all joints of affected legs. Results were then replicated using two human stem cell lines, one already in human trials for ALS. ... We obtained the exact results using human cells as we had in the rat cells."

Link: http://www.eurekalert.org/pub_releases/2012-09/uoc--nsc091012.php

LysoSENS is the oldest extant research program of the SENS Foundation, started back when the SENS program ran under the auspices of the Methuselah Foundation. In brief, LysoSENS is the development of a means of biomedical remediation. A whole range of harmful metabolic byproducts build up in human tissue with age, and we lack the means to break them down, or break them down fast enough. Some of these compounds simply cause harm, while others actually progressively impair the ability of cells to remove any unwanted chemicals, leading to what is known as the garbage catastrophe in aging - cells overwhelmed with broken protein machinery and waste products.

To do something about this issue we need ways to break down these waste products, such as those that make up lipofuscin, a mix of compounds that bloat and degrade the cellular recycling machinery known as lysosomes. Lipofuscin is implicated in a range of age-related diseases (as well as a class of genetic conditions known as lysosomal storage diseases). The LysoSENS project aims to discover bacterial enzymes capable of breaking down lipofuscin constituents and other important damaging compounds, and which can safely be introduced to human tissue. Researchers will then build a therapy to deliver these enzymes to where they are needed in our cells.

We have long known that such enzymes must exist, because places such as graveyards and battlefields do not exhibit a buildup of lipofuscin - something is eating it all. So the LysoSENS project started out by sifting through bacteria in soil samples, testing to see which of the bacterial species in the samples could consume harmful compounds such as 7-ketocholesterol, and then isolating the responsible enzymes.

This has been going on for a few years now, of course, and progress has been made - even at the all-too-low levels of funding available for this work. At this stage in the project a number of candidate enzymes that break down 7-ketocholesterol have been identified, and researchers are now putting them through their paces in cell cultures. One enzyme at least is worthy of a published paper.

Increased resistance to oxysterol cytotoxicity in fibroblasts transfected with a lysosomally targeted Chromobacterium oxidase

7-Ketocholesterol (7KC) is a cytotoxic oxysterol that plays a role in many age-related degenerative diseases. 7KC formation and accumulation often occurs in the lysosome, which hinders enzymatic transformations that reduce its toxicity and increase the sensitivity to lysosomal membrane permeabilization.

We assayed the potential to mitigate 7KC cytotoxicity and enhance cell viability by overexpressing 7KC-active enzymes in human fibroblasts. One of the enzymes tested, a cholesterol oxidase engineered for lysosomal targeting, significantly increased cell viability in the short term upon treatment with up to 50 µM 7KC relative to controls. These results suggest targeting the lysosome for optimal treatment of oxysterol-mediated cytotoxicity, and support the use of introducing novel catalytic function into the lysosome for therapeutic and research applications.

Some comments at the SENS Foundation:

The success of the approach employed by the team at Rice makes this enzyme, Chromobacterium sp. DS1 cholesterol oxidase, an important step toward a true rejuvenation biotechnology - a therapy that can target and repair damage that underlies the diseases and disabilities of the aging process. SENS Foundation is pleased to continue backing Dr. Mathieu's research, so that further work can move us closer to making such treatments a reality.

Given that many different harmful metabolic waste products exist, the field of biomedical remediation has enormous scope for growth - and certainly for more funding, which should hopefully start to arrive in the wake of proof of concept work like this. There is no need to slow down after finding one or more enzymes that break down 7-ketocholesterol, as firstly there could still be far better enzymes out there for this job, and secondly there remain numerous other damaging waste compounds in our cells and tissues that are worthy of biomedical remediation.

There is a school of thought that declares the average pace of degenerative aging as "normal" and states that any faster degenerations should be broken out and called "disease." This is somewhat manageable at the level of taxonomy, where you are only cataloging and describing the various ways in which bodily parts and systems break down, but as a system of thought it falls down badly once you have the ability to look under the hood to see what is going in our biochemistry. All of aging and age-related disease descend from the same collection of damage-causing processes, which like rust in a metal construction can lead to any number of different forms of ultimate structural failure - but all stemming from the same root causes. So trying to draw a dividing line between aging and disease produces issues and unnecessary additional work, especially if the researcher is trying to treat only "disease" but let "aging" progress, as you can see from the opening paragraphs in this paper: "Aging of the musculoskeletal system starts early and is detrimental to multiple functions of the whole organism, since it leads to disability and degenerative diseases. The age-related musculoskeletal changes are important in medical risk assessment and care because they influence the responses to treatment and outcomes of therapy. ... There are two major problems that one faces while trying to disentangle the biological complexity of the musculoskeletal aging: (a) it is a systemic, rather than 'compartmental,' problem, which should be dealt with accordingly, (b) the aging per se is neither well defined nor reliably measurable. A unique challenge of studying any age-related process is a need of distinguishing between the 'norm' and 'pathology,' which are interwoven in the aging. When another dimension is added, namely genetics underlying the system's functioning, even less is known about this aspect, and attempts to decipher genetic relationships between the system's components are few. ... To disentangle the aging-related pathology from the homeostasis particular for aging steady-state, is a challenging task. Despite the multiple definitions of the aging process were proposed, there is no single agreed upon and reliable measurement, therefore underlying molecular mechanism of aging is still not fully understood. The definition of aging is complicated by the occurrence of various diseases that modify body functions and tissue structures; these disease-related changes that are common in older persons are often hard to delineate from the aging process per se."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3429074/

Researchers here use stem cells to partially reverse of a form of deafness in laboratory animals: "Deafness is a condition with a high prevalence worldwide, produced primarily by the loss of the sensory hair cells and their associated spiral ganglion neurons (SGNs). Of all the forms of deafness, auditory neuropathy is of particular concern. This condition, defined primarily by damage to the SGNs with relative preservation of the hair cells, is responsible for a substantial proportion of patients with hearing impairment. Although the loss of hair cells can be circumvented partially by a cochlear implant, no routine treatment is available for sensory neuron loss, as poor innervation limits the prospective performance of an implant. Using stem cells to recover the damaged sensory circuitry is a potential therapeutic strategy. Here we present a protocol to induce differentiation from human embryonic stem cells (hESCs) using signals involved in the initial specification of the otic placode. We obtained two types of otic progenitors able to differentiate in vitro into hair-cell-like cells and auditory neurons that display expected electrophysiological properties. Moreover, when transplanted into an auditory neuropathy model, otic neuroprogenitors engraft, differentiate and significantly improve auditory-evoked response thresholds. These results should stimulate further research into the development of a cell-based therapy for deafness."

Link: http://dx.doi.org/10.1038/nature11415

A few genetic and metabolic commonalities have been uncovered in studies of the longest-lived families over the past decade, a part of the broader search for longevity genes and mechanisms in humans. Some of these involve the activity and levels of insulin-like growth factor IGF-1, something that is well studied by that part of the research community focused on the intersection of aging, genetics, and the operation of metabolism. Changes in IGF-1 biochemistry show up in many species and many interventions that alter life span, but despite an ocean of data gathered by various researchers, the sheer complexity of these metabolic processes ensures that there is still room to argue over how and why (or even if) IGF-1 influences lifespan.

For example, take a look at the introduction to the paper I'm going to point out today, wherein the authors skim over a set of contradictory results that show either higher and lower IGF-1 levels to be associated with human longevity, or no association at all:

Data on IGF-I system in relation to longevity are still controversial. Bonafè et al. previously found that subjects with at least an A allele of the IGF-I receptor (IGF-IR) gene (G/A, codon 1013) had low levels of free plasma IGF-I and were more represented among long-lived people. In contrast, Paolisso et al. found [evidence suggesting] a higher IGF-I bioavailability which contributed to the observed improved insulin action in centenarians. An overrepresentation of heterozygous mutations in the IGF-IR gene associated with high serum IGF-I levels and reduced activity of the IGF-IR has been reported in Ashkenazi Jewish centenarians compared to controls. In addition, in humans positive associations between circulating total IGF-I levels and cancer mortality have been found in many studies, while low total IGF-I levels have been associated with an increased risk for cardiovascular diseases and diabetes. On the other hand, Rozing et al. showed that offspring of familial nonagenarians displayed similar IGF-I and IGFBP-3 levels compared to their partners.

These conflicting results probably reflect the complexity of the IGF-system. We recently developed an IGF-I kinase receptor activation (KIRA) assay to assess circulating IGF bioactivity. This assay determines IGF-I bioactivity [and] unlike the traditional IGF-I immunoassays [it can be used] to measure the overall IGF-IR activation in blood.

So the authors here suggest that other researchers have been measuring values that don't reflect the true and complicated operation of the IGF-1 system, and produce an assay of their own that supposedly does better - by measuring a better proxy for the actual activity of IGF-1 and accounting for more confounding factors. The results from their data are as follows:

Low circulating IGF-I bioactivity is associated with human longevity: Findings in centenarians' offspring

Centenarians' offspring represent a suitable model to study age-dependent variables (e.g. IGF-I) potentially involved in the modulation of the lifespan. The aim of the present study was to investigate the role of the IGF-I in human longevity. We evaluated circulating IGF-I bioactivity measured by an innovative IGF-I Kinase Receptor Activation (KIRA) Assay ... In conclusion: 1) centenarians' offspring had relatively lower circulating IGF-I bioactivity compared to offspring matched-controls; 2) IGF-I bioactivity in centenarians' offspring was inversely related to insulin sensitivity. These data support a role of the IGF-I/insulin system in the modulation of human aging process.

If you look back in the Fight Aging! archives you'll find some discussion on how IGF-1 might influence life span in various species, such as through hormetic mechanisms relating to the mitochondria:

Signs of progress in understanding the mechanisms of induced longevity through altered insulin/IGF-1 signaling are shown in this paper. This is one of the most-studied class of longevity mutations in lower animals, despite there being some debate over whether it is relevant to mammal biochemistry. Here, the basic mechanism is explained as being hormetic, centering on the mitochondria: researchers elucidate a conserved mechanism through which reduced insulin-IGF1 signaling activates an AMP-kinase-driven metabolic shift toward oxidative proline metabolism. This, in turn, produces an adaptive mitochondrial [reactive oxygen species (ROS)] signal that extends worm life span. These findings further bolster the concept of mitohormesis as a critical component of conserved aging and longevity pathways.

Here is a good discussion on some common errors in the use of life expectancy data - such as mistaking period life expectancy (a statistical measure of health and medical technology) for cohort life expectancy (how long people actually live). It doesn't touch on the great uncertainty in predictions of future longevity due to the rapid pace of development in biotechnology, but is still an interesting read: "The US Government estimated its population had a life expectancy of 78.5 years in 2009. If you type 'life expectancy' into Google, it will spit back the World Bank estimate of 78.2 years in 2010. You've likely read numbers close to these in textbooks and articles. But what do these numbers actually mean? You might guess from the first that someone born in the United States in 2009 could be expected to live about 78.5 years. This is not the case! It actually measures how long someone would be expected to live if every year of their life was spent in 2009. In other words, there is no accounting for progress that decreases mortality rates. And that's on purpose. It is what is known as a 'period life expectancy'. Period life expectancies are used to track the general health of a population. With them you can easily compare one country to another. You can also monitor general population health over time. But the number you want if you'd like to know how long people will actually live is known as a 'cohort life expectancy'. It measures how long someone born in a particular year (a cohort) can be expected to live. It is also not in the US Government yearly mortality report for 2009. The reason is that we won't know it until everyone born in 2009 is dead! That will hopefully take a long long time."

Link: http://blog.edwardmarks.com/post/31337304505/life-expectancy-doesnt-measure-how-long-youre

Another form of cancer turns out to have a core of stem cells that can be targeted: "the research team generated cellular models of drug resistance by treating prostate tumor cell lines with increasing doses of the common chemotherapy drugs, including docetaxel. They identified a cell population expressing markers of embryonic development. In addition, these cells displayed cancer stem cell functions, including the capacity to initiate tumor cell growth. Next, the team evaluated human tissue samples of prostate cancer and found that patients with more aggressive or metastatic tumors had more of these cancer 'stem' cells. ... The study also defines a new therapeutic strategy for patients with prostate cancer, consisting of a combination of standard chemotherapy and two pharmacological agents that inhibit key signaling pathways associated with embryonic development and cell differentiation. Results showed that chemotherapy eliminated differentiated tumor cells, whereas the signaling pathway inhibitors selectively depleted the cancer stem cell population. Some of these inhibitors are already in clinical trials, and some are FDA-approved. ... By targeting these newly identified cancer 'stem' cells, we are attacking the foundation of tumor growth, rather than treating the symptoms of it."

Link: http://www.eurekalert.org/pub_releases/2012-09/tmsh-rra091012.php

Here is a point lifted from an essay by Maria Konovalenko of the Science for Life Extension Foundation:

If this generation dies, it dies only because of its own stupidity. Because it doesn't care about scientific research in the area of life extension. There is some research going on, but it's pace and the amount of funding is ridiculous compared to the importance of the goal.

It is possible that folk in middle age today, myself included, won't be able to take advantage of rejuvenation biotechnologies - if, for example, development continues to be funded poorly, broader public support for the reversal of aging fails to emerge, or the first thirty year cycle of research, development, and commercialization fails to produce meaningful results. As Aubrey de Grey notes, minimal levels of funding seem to be the most obvious and plausible blocking issue for the foreseeable future. The young have few such worries: they have time to wait out failed business cycles, slow-moving research, public opposition, and an economic collapse between now and when they would absolutely need rejuvenation therapies. A good fraction of the children born in the past few years will live a thousand years in youthful health and vigor, thanks to an upward, accelerating curve in biotechnology.

So from my perspective it is indeed the case that the only way today's young folk will die of aging is if they choose to do so - such as by failing to support the goal of engineered longevity because they believe that people should age and die, or because they haven't given much thought to living a life any different from that of their parents and grandparents, or because they choose to remain ignorant of medicine and its future. Those are all choices in the broadest sense, and possibly stupid, though it's worth considering that actual stupidity and mere lack of attention given to a particular topic look much the same from a distance.

Few of us pay more than a tiny amount of attention to anything beyond our specialties, but this is one of those rare eras in which a great deal hinges on paying attention to a specific field. The future of biotechnology has to potential to reshape and greatly extend all of our lives, and remaining ignorant or on the sidelines only adds to the chance that the necessary advances will arrive too late for us.

Researchers are making progress in growing replacement ears, using a mix of old and new methods in tissue engineering and reconstructive surgery: "Using a computer model of a patient's remaining ear, scientists craft a titanium framework covered in collagen, the stuff that gives skin elasticity and strength. They take a snip of cartilage from inside the nose or between the ribs and seed the scaffold with these cells. This is incubated for about two weeks in a lab dish to grow more cartilage. When it's ready to implant, a skin graft is taken from the patient to cover the cartilage and the ear is stitched into place. Scientists in her lab have maintained lab-grown sheep ears [for] 20 weeks, proving it can be done successfully and last long-term. They also have grown anatomically correct human ears from cells. These have been implanted on the backs of lab rats to keep them nourished and allow further research. ... Now they are ready to seek approval from the Food and Drug Administration to implant these into patients - probably in about a year."

Link: http://www.boston.com/lifestyle/health/2012/09/09/impact-surprising-methods-heal-wounded-troops/8l1mjXFfwTJ1ry2RN58cQI/story.html

News of an advance in the understanding of atherosclerosis: "Researchers [are] one step closer to understanding why plaque bursts in coronary arteries and causes heart attacks. The clue might be something called microRNA-145. MicroRNAs are short chains of bossy molecules that scientists are increasingly coming to realize control a wide variety of biological processes. ... most heart attacks occur when plaques rupture like a broken eggshell and release their contents into the artery. Researchers are therefore looking for ways to reduce the size of plaques and make them more stable. One of the key questions is what causes the outer layer of the plaque to finally burst - a layer of smooth muscle cells known as the fibrous cap. These cells undergo 'phenotypic transformation' in response to various stressful environments and cardiovascular risk factors, making them more likely to rupture and cause heart attacks. MicroRNA-145 is one of the factors that appear to play a critical role in preventing the transformation of vascular smooth muscle cells into rupture-prone cells. In atherosclerosis-prone animals, microRNA-145-based gene therapy reduced the plaque size by approximately 50 per cent and increased the collagen content of the plaque and fibrous cap area by 40 to 50 per cent, indicating that this therapy can reduce plaque buildup and also make it less prone to rupture, the inciting event of heart attacks. The researchers also found that in human atherosclerotic plaques, the amount of microRNA-145 was reduced compared to normal arteries that were free of plaque, providing supporting human insights to the animal study."

Link: http://www.stmichaelshospital.com/media/detail.php?source=hospital_news/2012/20120910_hn

With all of the media attention presently (and no doubt temporarily) given to the practice of calorie restriction, I thought I'd point out an interesting open access paper on this topic. Comparatively little of the literature on calorie restriction that passes through my neck of the woods is written from the perspective of the cancer research community, so you may find references to research results you weren't previously aware in this review.

Insights into the beneficial effect of caloric/ dietary restriction for a healthy and prolonged life:

Over the last several years, new evidence has kept pouring in about the remarkable effect of caloric restriction (CR) on the conspicuous bedfellows - aging and cancer. Through the use of various animal models, it is now well established that by reducing calorie intake one can not only increase life span but, also, lower the risk of various age related diseases such as cancer.

Cancer cells are believed to be more dependent on glycolysis for their energy requirements than normal cells and, therefore, can be easily targeted by alteration in the energy-metabolic pathways, a hallmark of CR. Apart from inhibiting the growth of transplantable tumors, CR has been also shown to inhibit the development of spontaneous, radiation, and chemically induced tumors.

The question regarding the potentiality of the anti-tumor effect of CR in humans has been in part answered by the resistance of a cohort of women, who had suffered from anorexia in their early life, to breast cancer. However, human research on the beneficial effect of CR is still at an early stage and needs further validation.

Though the complete mechanism of the anti-tumor effect of CR is far from clear, the plausible involvement of nutrient sensing pathways or IGF-1 pathways proposed for its anti-aging action cannot be overruled. In fact, cancer cell lines, mutant for proteins involved in IGF-1 pathways, failed to respond to CR. In addition, CR decreases the levels of many growth factors, anabolic hormones, inflammatory cytokines, and oxidative markers that are deregulated in several cancers.

The authors go on to discuss the means by which calorie restriction might beneficially impact the odds and progress of cancer. There is a great deal of data, but room enough in the remaining uncertainty to argue the case for calorie restriction's effects on cancer to be caused by either (a) the same mechanisms as extend longevity, or (b) some completely different set of mechanisms. There is plenty of room for writing grants here also, given the growing willingness of funding bodies to pay for research into the many and complex relationships that link metabolism with aging and longevity.

Now if the research community would only pay as much attention to plans for research that might actually extend life significantly, rather than just obtain more data on the operation of the human body...

Our muscles decline with age for reasons that seem likely to soon be treatable. Finding ways to retain muscle mass and strength would hopefully allow older people to continue to be active and exercising, thus removing this contribution to the frailty that leads into a downward spiral of health in late life: "Changing demographics make it ever more important to understand the modifiable risk factors for disability and loss of independence with advancing age. For more than two decades there has been increasing interest in the role of sarcopenia, the age-related loss of muscle or lean mass, in curtailing active and healthy aging. There is now evidence to suggest that lack of strength, or dynapenia, is a more constant factor in compromised wellbeing in old age and it is apparent that the decline in muscle mass and the decline in strength can take quite different trajectories. ... An understanding of the impact of aging on skeletal muscle will require attention to both the changes in muscle size and the changes in muscle quality. ... Cross-sectional studies comparing young (18-45years) and old (older than 65years) samples show dramatic variation based on the technique used and population studied. The median of values of rate of loss reported across studies is 0.47% per year in men and 0.37% per year in women. Longitudinal studies show that in people aged 75years, muscle mass is lost at a rate of 0.64-0.70% per year in women and 0.80-00.98% per year in men. Strength is lost more rapidly. Longitudinal studies show that at age 75years, strength is lost at a rate of 3-4% per year in men and 2.5-3% per year in women. Studies that assessed changes in mass and strength in the same sample report a loss of strength 2-5 times faster than loss of mass. Loss of strength is a more consistent risk for disability and death than is loss of muscle mass."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3429036/

From Wired: "Over the past decade, the main areas of research - brain emulation, regenerative medicine and cryonics - have gradually been departing the realms of science fiction and making a name for themselves in scientific journals. Back in 2009, when Avatar suggested that people could one day upload their brain to an invincible body-double, it seemed like something only James Cameron could dream up. Then a student in Israel controlled a robot with his mind from 2,000km away. In 2009 Aubrey de Grey announced - to more than a few raised eyebrows - that the first person to live to 1,000 thanks to regenerative medicine was probably already alive - and by 2012 a four-year old became the first person to receive a life-saving blood vessel made from her own cells. And around about the same time the horrendous 1997 film Batman & Robin painted cryonics as a field best reserved for psychotic villains, Gregory Fahy and William Rall announced the development of the first cryoprotectant able to vitrify the human body slowly enough that ice crystals don't form and cause tissue damage. ... The 1,000 year life span [Aubrey de Grey] is predicting will be the norm is explained by a straightforward calculation: 'we just look at how often people in the industrialised world die today of causes that are not related to ageing -- if you get to the age of 26, your chances of not getting to 27 is less than one in a thousand.' And how would the planet look with this evergreen, undying population? de Grey is not too worried about that, and is clearly incredulous that anyone else would be. For one thing, if the age women are choosing to have children is already rapidly on the rise, it stands to reason this trend will continue. Menopause won't be an issue, neither will natural resources - by the time we have to worry about a rapidly-growing population, technology will have advanced to cope with the factors we battle today. It could come down to a future universal equivalent of China's one-child policy, but whatever the solution, de Grey says it is ultimately our obligation to give humanity the choice. 'I want to make the choice whether I want to live to 100 when I'm 99, rather than having that choice progressively removed from me by my declining health.'"

Link: http://www.wired.co.uk/news/archive/2012-09/08/life-extension?page=all

A couple of generally useful large reference studies on body weight, level of exercise, and resulting life expectancy and lifetime medical costs have shown up in recent years. As I'm sure you all know by now, the data all points in the direction of more fat and less exercise correlating with a shorter, less healthy life and higher lifetime medical costs. Take a look at these items, for example:

• Exercise, Longevity, and Long Term Medical Costs
• More Health, Longevity, and Medical Cost Data from the Ohsaki Cohort Study
• Another Look at the Economics of Inactivity

I recently noticed another, similar study on the Israeli population:

Health care costs per person were calculated by body mass index (BMI) by applying Israeli cost data to aggregated results from international studies. These were applied to BMI changes from eight intervention programmes in order to calculate reductions in direct treatment costs. Indirect cost savings were also estimated as were additional costs due to increased longevity of program participants. Data on costs and Quality-Adjusted Life Years (QALYs) gained from Israeli and International dietary interventions were combined to provide cost-utility estimates of an intervention program to reduce obesity in Israel.

...

On average, persons who were overweight (25 ≤ BMI < 30)had health care costs that were 12.2% above the average health care costs of persons with normal or sub-normal weight to height ratios (BMI < 25). This differential in costs rose to 31.4% and 73.0% for obese and severely obese persons, respectively.

I imagine that the popularity of this sort of work of late, or at least the increased willingness of funding bodies to make the necessary grants, has to do with a greater awareness of the impending financial collapse in medical entitlements and centralized health systems. This sad end is somewhat inevitable whenever a system is set up such that patients do not bear costs directly and funds are drawn from taxed resources - there will be overspending, waste, spiraling prices, special interests and all the other ugly aspects of business as usual in politics.

The "solution" offered up by the talking heads is, as usual, more control over everything: rationing, expensive attempts to influence lifestyle choices, and so forth. A far better option, and one unlikely to be tried until these systems have decayed into the sort of wasteland commonly associated with the ruins left at the end of the Soviet era, is simply to let people buy and sell medical services unmolested, unregulated, and in open competition. But that offers those in power few opportunities to advance their own position and line their own pockets, so as you can imagine it doesn't have many advocates where it matters. But ultimately the money runs out and the promises cannot be kept; if something cannot be paid for then it will not be paid for, regardless of how pretty the lies and promises might be.

So two lessons here: firstly, don't get fat and don't stay fat. Secondly, don't expect anyone to be paying your way in later life, regardless of what government employees might have to say on the matter.

It's been a while since nanog was discussed here; it's one of the genes associated with early efforts to reprogram somatic cells into stem cells and seems to be important in the activity of embryonic stem cells. Here researchers are investigating the reversal of stem cell aging: "Although the therapeutic potential of mesenchymal stem cells (MSC) is widely accepted, loss of cell function due to donor aging or culture senescence are major limiting factors hampering their clinical application. Our laboratory recently showed that MSC originating from older donors suffer from limited proliferative capacity and significantly reduced myogenic differentiation potential. This is a major concern, as the patients most likely to suffer from cardiovascular disease are elderly. Here we tested the hypothesis that a single pluripotency associated transcription factor, namely Nanog, may reverse the proliferation and differentiation potential of BM-MSC from adult donors. Microarray analysis showed that [expressing Nanog] markedly upregulated genes involved in cell cycle, DNA replication and DNA damage repair and enhanced the proliferation rate and clonogenic capacity of [adult] BM-MSC. Notably, Nanog reversed the myogenic differentiation potential and restored the contractile function of [adult] BM-MSC to a similar level as that of neonatal BM-MSC. ... Overall, our results suggest that Nanog may be used to overcome the effects of organismal aging on BM-MSC, thereby increasing the potential of MSC from aged donors for cellular therapy and tissue regeneration."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22949105

An interesting view on the evolutionary depths of longevity in mammals, achieved through analysis of presently available genomes: "It is widely assumed that our mammalian ancestors, which lived in the Cretaceous era, were tiny animals that survived massive asteroid impacts in shelters, and evolved into modern forms after dinosaurs went extinct, 65 Mya. The small size of most Mesozoic mammalian fossils essentially supports this view. Paleontology, however, is not conclusive regarding the ancestry of extant mammals, because Cretaceous and Paleocene fossils are not easily linked to modern lineages. Here we use full-genome data to estimate the longevity and body mass of early placental mammals. Analysing 36 fully-sequenced mammalian genomes, we reconstruct two aspects of the ancestral genome dynamics ... Linking these molecular evolutionary processes to life history traits in modern species, we estimate that early placental mammals had a life-span above 25 years, and a body mass above one kilogram. This is similar to current primates, cetartiodactyls or carnivores, but markedly different from mice or shrews, challenging the dominant view about mammalian origin and evolution. Our results imply that long-lived mammals existed in the Cretaceous era, and were the most successful in evolution, opening new perspectives about the conditions for survival to the Cretaceous-Tertiary crisis."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22949523

A recent open access paper points to changing cytokine levels as a candidate mechanism for a range of conditions that occur with age and are generally made either worse or more likely by the presence of excess fat tissue. The link between being overweight and a higher risk of suffering the common age-related conditions is well known; chronic inflammation is thought to be an important mechanism here due to the way in which it impacts so many different systems in our biology, but the exact details are still open to debate.

Sarcopenia, obesity, and natural killer cell immune senescence in aging: Altered cytokine levels as a common mechanism

An inevitable consequence of human and rodent aging is sarcopenia - loss of muscle mass. Some muscle loss is due to physical inactivity, but even highly trained athletes lose muscle mass and strength with age. Although exercise programs can prevent and/or ameliorate sarcopenia, the effectiveness of exercise interventions to build muscle and effect metabolic improvements is less efficient in elderly subjects than in the young, due to multiple cellular and biochemical changes. ... Adipose tissue gain also is very common in aging and is a growing health concern for all ages. Visceral (abdominal) fat is of the greatest health concern because it is associated with insulin resistance, type 2 diabetes, cardiovascular disease, dementia, cancer, and overall mortality. ... Furthermore, obesity prevents muscle gain in response to functional overload [and] the combination of obesity and sarcopenia (so-called sarcopenic obesity) carries high health risks.

Another hallmark of aging is declining adaptive immunity, with complex alterations in innate immunity. Immune senescence is associated with mortality from all causes, including infectious diseases. Natural killer (NK) lymphocytes are innate immune cells that control intracellular infectious agents and cancers. In contrast to T and B lymphocytes, NK cell number is relatively increased in healthy aging and defects in NK cell function are subtle. However, declining NK cell number or function in aging is associated with death in the elderly. Therefore, mechanisms that preserve NK cell number and function may promote healthy aging.

To relate sarcopenia, obesity, and declining immunity in aging, we speculated that these conditions are linked processes, which are controlled by adipose tissue-derived and skeletal muscle-derived cytokines, known as adipokines and myokines, respectively

You can't really control the degree to which your immune system has been and will be hammered by various common herpesviruses, such as the near-omnipresent cytomegalovirus, but do you have a great deal of control over the fat tissue end of the relationship proposed in this paper. Letting yourself go to seed, getting fat and unfit, has consequences in the long term: a shorter, less healthy life with higher medical bills. Maybe science and those medical costs will dig you out of this hole before it kills you, but why roll those dice if you don't have to? The future of aging, health, and the biotechnologies of rejuvenation on the horizon is already uncertain enough for those of us in middle age today. Every extra year you can gain might make the difference between taking advantage of the first therapies to reverse aging and missing that boat entirely.

This chart from the Scientific American clearly illustrates the progress in tackling heart disease over the past few decades, a factor that is driving a steady rise in life expectancy at older ages. Mortality rates for this range of conditions are falling quite dramatically: "A baby born in the U.S. this year is likely to live to blow out 78 birthday candles - a far longer average life span than someone born even in the 1960s. Heart disease is still the biggest killer but it, along with fatal infectious diseases and infant mortality have all fallen to much lower levels in the past half century. Researchers are now hard at work tackling the growing afflictions, such as nervous system diseases and Alzheimer's, which are far more likely to attack the ever more senescent population. ... Researchers are exploring two main approaches to extending healthy human life span. One camp believes we should focus on curing disease and replacing damaged body parts via stem cell therapies. Another camp believes we must slow the aging process on the cellular and molecular levels." If you include the SENS approach to repair of the causes of aging under "curing disease and replacing damaged body parts", then this describes the most important issue of our time in the life sciences: will the research community take an effective path or not in the treatment of aging? This will determine how long we all live.

Link: http://www.scientificamerican.com/article.cfm?id=longevity-why-we-die-global-life-expectancy

Via ScienceDaily: "Scientists have found that eliminating an enzyme from mice with symptoms of Alzheimer's disease leads to a 90 percent reduction in the compounds responsible for formation of the plaques linked to Alzheimer's disease. ... The key to reducing A-beta peptides was the elimination of an enzyme called jnk3. This enzyme stimulates a protein that produces A-beta peptides, suggesting that when jnk3 activities are high, A-beta peptide production increases - increasing chances for their accumulation and formation into plaques. The researchers also observed that jnk3 activities in brain tissue from Alzheimer's disease patients were increased by 30 to 40 percent when compared to normal human brain tissue. Jnk3 activity typically remains low in the brain, but increases when physiological abnormalities arise. ... [Researchers] deleted jnk3 genetically from Alzheimer's disease model mice carrying the mutations that are found among early-onset Alzheimer's disease patients. In six months, the deletion of the enzyme had lowered A-beta peptide production by 90 percent, which persisted over time, with a 70 percent reduction seen at 12 months in these mice. When the researchers saw that elimination of jnk3 dramatically lowered A-beta peptides in the mice, they also looked for effects on cognitive function at 12 months. The deletion of jnk3 improved cognitive function significantly, reaching 80 percent of normal, while cognitive function in disease model mice was 40 percent of normal. The number of brain cells, or neurons, in the Alzheimer's disease mice was also increased with jnk3 deletion, reaching 86 percent of the value in normal mice, while the neuron numbers were only 74 percent in Alzheimer's model mice."

Link: http://www.sciencedaily.com/releases/2012/09/120905122750.htm

Accumulation of excess body fat is easy to accomplish in a wealthy society, and it has very unpleasant consequences over the long term. The more time you spend carrying additional visceral fat tissue, the higher your risk of suffering all of the common age-related diseases in later life, the greater your expected medical bills, and the shorter your life expectancy. This is all well understood and widely ignored: the urges to eat and laze are strong in the average human.

The way in which our bodies grasp at nutrients and aggressively store any excess as fat tissue didn't evolve because it is harmful, however. It evolved because it provides an advantage to survival and propagation of the species - at least it did while we occupied an evolutionary niche characterized by unreliable access to food. When we leave that niche for one with reliably abundant nutrition, these metabolic mechanisms become a maladjustment. We have succeeded ourselves out of the obvious and ugly scenarios of famine and into the more subtle scenarios of self-sabotage. Change in our environment is now self-directed and far faster than evolution can keep up with: we are the masters of our own destiny, and what goes on in our heads becomes more important than many other factors when it comes to health, longevity, and our environment.

Here is an open access paper that goes into some detail on this theme:

The pan-human profile of adiposity was shaped over our evolutionary past, reflecting ecological pressures that favored a number of unusual traits that are characteristic of our species, [widely] assumed to have been favored by the emerging 'savannah' environment in east and southern Africa. There is a tendency to consider the savannah a relatively stable environment, with our modern fast-changing urban environment generating a stark sudden contrast. An increasing volume of palaeoenvironmental data suggests that this view of past stability is very misleading ... Although outright famines might have been rare in pre-agricultural populations, and severe food shortages could be addressed by nomadism, hominin populations can be assumed to have experienced energy stress repeatedly across and within generations, resulting from various cycles of uncertainty. These include seasonality, longer-term systematic climate shifts, and extreme events such as volcanic eruptions and climatic cycles.

...

We can therefore consider adipose tissue as a strategy for energy storage that responds to multiple ecological stresses ... Storing energy as fat is by no means the only strategy for managing the risk of uncertainty in energy supply. A highly social organism such as humans can store energy not only in the body but also extra-corporally (in food hoards) or in social relationships. This 'redundancy' of multiple mechanisms suggests that energy risk management was crucial in the evolution of our species.

...

The fact that adipose tissue is the source of numerous signaling molecules highlights its role in orchestrating life-history decisions. This risk management system is, however, increasingly destabilized in many human populations. Prevailing economic policies cause individuals to be subjected to a range of 'invasive' cues favoring fat accumulation, in environments in which actual energy availability has high stability. The combination of insulinogenic diets and psychosocial stress on the one hand, and low energy demand for physical exertion, reproduction and immune function on the other, stimulates chronic lipogenesis but reduces lipolysis. At this point, high levels of adiposity become toxic and harmful to health. It is these socio-environmental cues, collectively orchestrated by our capitalist economic system, that are the optimal target for obesity prevention.

As noted above this researcher recommends efforts to be directed towards some form of intervention in society rather than new medicine; this is actually a fairly commonplace attitude, sad to say. Examples include calls for regulation of advertising or consumption - strategies well-documented to have failed miserably in wealthy societies as far back as Medieval France and ancient China. Interfering in free enterprise tends to destroy wealth - the most effective means of reducing consumption is to induce poverty throughout a society. This approach and all of its unpleasant side-effects have also been well-demonstrated, such as in the ruins produced of Russian progress and well-being during the communist era.

Freedom and the creation of sufficient wealth to produce widespread health issues go hand in hand - but are also accompanied by all the myriad benefits of wealth, such as advanced medicine, comfort, and choice. A wealthy society whose elites attain a centralized grip on power sufficient to dictate the diet and lifestyle of citizens will not long remain wealthy, as that level of regulatory and enforcement power is a cancer that spreads and kills the means by which progress happens. On the flip side of the coin, in a free society the costs of self-inflicted health issues (or insurance against those costs) are borne by the individual, serving as one counterbalancing incentive against a bad lifestyle. More importantly, the right to make bad choices and suffer their consequences is respected insofar as they hurt only the individual making them.

We evolved for a brutal environment of failure and poverty, and thus we are poorly adapted for success and wealth - but that isn't just a matter of fat tissue. Human psychology is also an issue, evolved for an age of small hunter-gatherer groups, and our instinctive attitudes towards strangers, success, inequality, and freedom cause great harm when put into practice in an age of cities and wealth. See, for example, the urge to control the actions of others that feeds the growth and centralization of regulatory states.

So at the bottom line, I think that a technological solution is the best way to dig our way out of being physically poorly adapted to success. Other strategies will either be ineffective (e.g. advocacy for better lifestyles, which would have worked already if it was going to work) or threaten the very foundations of the wealth and success that creates these unfortunate side-effects on health. There are many possible paths ahead here, some harder than others, but all basically plausible: create some form of empty-calorie bulk that can be added to any form of food; alter human metabolism; build nanomachinery or engineered bacteria to live in the gut and keep food out of our reach; and so forth. I'm sure you can think of others.

In recent years a build up of α-synuclein has been shown to be important in some neurodegenerative conditions: "The discovery of α-synuclein has had profound implications concerning our understanding of Parkinson's disease (PD) and other neurodegenerative disorders characterized by α-synuclein accumulation. In fact, as compared with pre-α-synuclein times, a "new" PD can now be described as a whole-body disease in which a progressive spreading of α-synuclein pathology underlies a wide spectrum of motor as well as nonmotor clinical manifestations. Not only is α-synuclein accumulation a pathological hallmark of human α-synucleinopathies but increased protein levels are sufficient to trigger neurodegenerative processes. α-Synuclein elevations could also be a mechanism by which disease risk factors (e.g., aging) increase neuronal vulnerability to degeneration. An important corollary to the role of enhanced α-synuclein in PD pathogenesis is the possibility of developing α-synuclein-based biomarkers and new therapeutics aimed at suppressing α-synuclein expression. The use of in vitro and in vivo experimental models, including transgenic mice overexpressing α-synuclein and animals with viral vector-mediated α-synuclein transduction, has helped clarify pathogenetic mechanisms and therapeutic strategies involving α-synuclein. These models are not devoid of significant limitations, however. Therefore, further pursuit of new clues on the cause and treatment of PD in this post-α-synuclein era would benefit substantially from the development of improved research paradigms of α-synuclein elevation."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22944910

A review paper: "Aging and reproduction are two defining features of our life. Historically, research has focused on the well-documented decline in reproductive capacity that accompanies old age, especially with increasing maternal age in humans. However, recent experiments in model organisms such as worms, flies and mice have shown that a dialogue in the opposite direction may be widely prevalent, and that signals from reproductive tissues have a significant effect on the rate of aging of organisms. This pathway has been described in considerable detail in the nematode Caenorhabditis elegans. Molecular genetic studies suggest that signals from the germline control a network of transcriptional regulators that function in the intestine to influence longevity. This network includes conserved, longevity-promoting Forkhead Box (FOX)-family transcription factors such as DAF-16/FOXO and PHA-4/FOXA, nuclear hormone receptors (NHRs) as well as a transcription elongation factor, TCER-1/TCERG1. Genomic and targeted molecular analyses have revealed that these transcription factors modulate autophagy, lipid metabolism and possibly other cellular processes to increase the length of the animal's life."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22945891

I'm a first things first sort of a person. A tremendous amount of work remains on any path that leads to the creation of rejuvenation biotechnology capable of reversing aging - especially if we want to it arrive before we die of old age - so expending a lot of effort on thinking about what happens afterwards doesn't strike me as helpful. That said, it can't hurt to glance ahead here and there in order to anticipate the next array of possible challenges and endeavors.

So this is one of those short glances, focused on the narrow issue of swimming upstream against the culture of our time - which is a great deal more work and a great deal slower than going with the flow.

As I'm sure you've all noticed, the currents of opinion and conversation that underpin our society are largely opposed to initiatives aimed at abolishing aging through medical science so as to live far longer healthy lives. To a certain extent this is because human societies are reflexively conservative, even in times of great change, and everything new is resisted, ridiculed, or ignored in the hope that it will go away, even if beneficial. The ape inside all of us lusts for stability and stasis. Another factor is that many people seem genuinely uninterested in ensuring more healthy time spent alive at some point decades from now - the psychology of time preference at work, deeply discounting the value of anything likely to happen a long time from now. Further, the greater the level of regulation and government intervention in a field, the slower it goes and the more that all change is opposed - just look at medicine in the US, for example, where the primary regulatory body does pretty much all it can to sabotage any form of progress in medicine.

One day, the change that was hard-won will be the new normal and completely accepted. That will be the case for longevity science and the defeat of aging as well, and people of the future will wonder how we could have been such barbarians, resisting the obvious benefits of not suffering, decaying, and dying. Until that time, supporting rationality and faster development in engineered human longevity will continue to be harder than it should be.

This additional cost in time and resources imposed by the nature of our present culture is an existential threat. It threatens to kill us by ensuring that the development of effective ways to reverse aging in the old arrive too late. Given that progress in this field of science and technology is a matter of persuading funding sources and raising money to accomplish known goals, it could be argued that this is a fight to change the prevailing culture rather than a matter of research. If we want to live, it's a fight we have to win - or at least convince a few tens of millions to become supporters of longevity science in the same way that most people are supporters of cancer research.

But let us look to the future, at what I see as a loosely analogous cultural battle that will start to arrive at around the same time as the means to reverse aging - one that will also present an existential threat to personal survival.

Consider that at some point in the next few decades it will become possible to simulate and then emulate a human brain. That will enable related technological achievements as reverse engineering of memory, a wide range of brain-machine interfaces, and strong artificial intelligence. It will be possible to copy and alter an individual's mind: we are at root just data and operations on that data. It will be possible for a mind to run on computing hardware rather than in our present biology, for minds to be copied from a biological brain, and for arbitrary alterations of memory to be made near-immediately. This opens up all of the possibilities that have occupied science fiction writers for the past couple of decades: forking individuals, merging in memories from other forks, making backups, extending a human mind through commodity processing modules that provide skills or personality shards, and so on and so forth.

There is already a population of folk who would cheerfully take on any or all of these options. I believe that this population will only grow: the economic advantages for someone who can edit, backup, and fork their own mind are enormous - let alone the ability to consistently take advantage of a marketplace of commodity products such as skills, personalities, or other fragments of the mind.

But you'll notice I used what I regard as a malformed phrase there: "someone who can edit, backup, and fork their own mind." There are several sorts of people in the world; the first sort adhere to some form of pattern theory of identity, defining the self as a pattern, wherever that pattern may exists. Thus for these folk it makes sense to say that "my backup is me", or "my fork is me." The second sort, and I am in this camp, associate identity with the continuity of a slowly changing arrangement of mass and energy: I am this lump of flesh here, the one slowly shedding and rebuilding its cells and cellular components as it progresses. If you copy my mind and run it in software, that copy is not me. So in my view you cannot assign a single identity to forks and backups: every copy is an individual, large changes to the mind are equivalent to death, and it makes no sense to say something like "someone who can edit, backup, and fork their own mind."

A copy of you is not you, but there is worse to consider: if the hardware that supports a running brain simulation is anything like present day computers, that copy isn't even particularly continuous. It is more like an ongoing set of individuals, each instantiated for a few milliseconds or less and then destroyed, to be replaced by yet another copy. If self is data associated with particular processing structures, such as an arrangement of neurons and their connections, then by comparison a simulation is absolute different: inside a modern computer or virtual machine that same data would be destroyed, changed, and copied at arbitrary times between physical structures - it is the illusion of a continuous entity, not the reality.

That should inspire a certain sense of horror among folk in the continuity of identity camp, not just because it is an ugly thing to think about, but because it will almost certainly happen to many, many, many people before this century ends - and it will largely be by their own choice, or worse, inflicted upon them by the choice of the original from whom the copy was made.

This is not even to think about the smaller third group of people who are fine with large, arbitrary changes to their state of mind: rewriting memories, changing the processing algorithms of the self, and so on. At the logical end of that road lie hives of software derived from human minds in which identity has given way to ever-changing assemblies of modules for specific tasks, things that transiently appear to be people but which are a different sort of entity altogether - one that has nothing we'd recognize as continuity of identity. Yet it would probably be very efficient and economically competitive.

The existential threat here is that the economically better path to artificial minds, the one that involves lots of copying and next to no concern for continuity of identity, will be the one that dominates research and development. If successful and embedded in the cultural mainstream, it may squeeze out other roads that would lead to more robust agelessness for we biological humans - or more expensive and less efficient ways to build artificial brains that do have a continuity of structure and identity, such as a collection of artificial neurons that perform the same functions as natural ones.

This would be a terrible, terrible tragedy: a culture whose tides are in favor of virtual, copied, altered, backed up and restored minds is to my eyes little different from the present culture that accepts and encourages death by aging. In both cases, personal survival requires research and development that goes against the mainstream, and thus proceeds more slowly.

Sadly, given the inclinations of today's futurists - and, more importantly, the economic incentives involved - I see this future as far more likely than the alternatives. Given a way to copy, backup, and alter their own minds, people will use it and justify its use to themselves by adopting philosophies that state they are not in fact killing themselves over and again. I'd argue that they should be free to do so if they choose, just the same as I'd argue that anyone today should be free to determine the end of his or her life. Nonetheless, I suspect that this form of future culture may pose a sizable set of hurdles for those folk who emerge fresh from the decades in which the first early victories over degenerative aging take place.

Muscle mass and strength decline with age, and researchers continue to explore the mechanisms by which this happens: "Skeletal muscle regeneration following injury is accompanied by rapid infiltration of macrophages, which play a positive role in muscle repair. Increased chronic inflammation inhibits the regeneration of dystrophic muscle, but the properties of inflammatory cells are not well understood in the context of normal muscle aging. This work uncovers pronounced age-specific changes in the expression of osteopontin (OPN) in CD11b+ macrophages present in the injured old muscle as well as in the blood serum of old injured mice and in the basement membrane surrounding old injured muscle fibers. Furthermore, young CD11b+ macrophages enhance regenerative capacity of old muscle stem cells even when old myofibers and old sera are present; and neutralization of OPN similarly rejuvenates the myogenic responses of old satellite cells in vitro and notably, in vivo. This study highlights potential mechanisms by which age related inflammatory responses become counter-productive for muscle regeneration and suggests new strategies for enhancing muscle repair in the old."

Link: http://impactaging.com/papers/v4/n8/full/100477.html

Via the New Scientist: "For the first time, people with broken spines have recovered feeling in previously paralysed areas after receiving injections of neural stem cells. Three people with paralysis received injections of 20 million neural stem cells directly into the injured region of their spinal cord. The cells, acquired from donated fetal brain tissue, were injected between four and eight months after the injuries happened. The patients also received a temporary course of immunosuppressive drugs to limit rejection of the cells. None of the three felt any sensation below their nipples before the treatment. Six months after therapy, two of them had sensations of touch and heat between their chest and belly button. The third patient has not seen any change. ... The fact we've seen responses to light touch, heat and electrical impulses so far down in two of the patients is very unexpected. They're really close to normal in those areas now in their sensitivity. ... The sensory gains, first detected at three months post-transplant, have now persisted and evolved at six months after transplantation. We clearly need to collect much more data to demonstrate efficacy, but our results so far provide a strong rationale to persevere with the clinical development of our stem cells for spinal injury. ... We need to keep monitoring these patients to see if feeling continues to affect lower segments of their bodies. These are results after only six months, and we will follow these patients for many years. ... There could be several reasons why the stem cells improve sensitivity ... They might help to restore myelin insulation to damaged nerves, improving the communication of signals to and from the brain. Or they could be enhancing the function of existing nerves, replacing them entirely or reducing the inflammation that hampers repair."

Link: http://www.newscientist.com/article/dn22235-stem-cells-bring-back-feeling-for-paralysed-patients.html

As I'm sure you noticed, the latest data from one of the two long-running primate studies of calorie restriction is being presented in the press as a negative result: no extension of mean life span in the rhesus monkeys in that study. This contrasts with another study that may or may not presently show a modest extension of primate life span with calorie restriction, depending on how you feel about the way in which the researchers are interpreting their data.

The press are largely running with "calorie restriction doesn't work," but that's because the mainstream media is shallow, either reprinting a superficial summary or at best treating each new research result in isolation rather than considering it in the context of the field as a whole. Doing the job properly, employing actual knowledge and analysis, takes more time and doesn't sell any more papers - so why bother? This is why the media should chiefly be used as a flagging mechanism; if you see discussion of a topic, note that it happened and then do your own research and analysis.

In science, each new set of data and consequent analysis should be added to the existing array for a given topic. Progressing towards a greater understanding is an incremental affair, especially given than a large proportion of studies and data are flawed in some way:

The scientific community doesn't produce an output of nice, neat tablets of truth, pronouncements come down from the mountain, however. It produces theories that are then backed by varying weights of evidence: a theory with a lot of support stands until deposed by new results. But it's not that neat in practice either. The array of theories presently in the making is a vastly complex and shifting edifice of debate, contradictory research results, and opinion. You might compare the output of the scientific community in this sense with the output of a financial market: a staggeringly varied torrent of data that is confusing and overwhelming to the layperson, but which - when considered in aggregate - more clearly shows the way to someone who has learned to read the ticker tape.

So what should we take away from the results of the two ongoing primate studies of life span and health under calorie restriction? After two decades one shows a modest boost to life span, the other no increase, and both show health benefits resulting from calorie restriction - though to different degrees. The control groups are fed differently, one allowed to eat as much as they like, the other on a set diet that has more calories than the restricted group. The composition of the diets in the two studies are also different. Even the genetic heritage of the rhesus monkeys involved is different enough for scientists to consider it significant, given the many but tenuous relationships to longevity found in the human genome over the past decade.

When looking beyond these studies to the broader context of data derived from a range of human studies and countless studies in mice, we see that calorie restriction absolutely, definitely has a large positive impact on health and longevity in shorter-lived mammals, and a large positive impact on measures of health in humans.

The first important point to consider is that these studies add to the weight of data and theory suggesting the effect of calorie restriction on the life span of longer-lived primates is small. Consider that any study is going produce results somewhere statistical map of what is possible and plausible: if two studies both show no extension or only a modest extension of life, then there would have to be a good reason to continue to believe that a large extension of life is possible. This concurs with the present scientific consensus and reasonable expectations: if calorie restriction could produce a 40% extension of maximum human life span, as it does in mice, then we'd have known about it since the age of antiquity. Our history is rife with cloistered groups that practiced austere lifestyles, after all, and many of them existed in periods of comparative wealth wherein suitable levels of nutrition were readily available.

A second important point is that this latest primate data in no way detracts from the health benefits produced by calorie restriction and demonstrated in numerous human studies. These research results are impressive: if calorie restriction were a drug, people would be falling over themselves to get a hold of it, as it leads to benefits that go far beyond anything that medical science can presently offer a basically healthy individual.

The future of calorie restriction research at the level of investigation and understanding - as opposed to attempts to build calorie restriction mimetic drugs - will, I suspect, involve a great deal of thought on how to reconcile significant beneficial effects on measures of health and disease risk with an apparently small beneficial effect on life span. That isn't an intuitive outcome given the view of aging as an accumulation of damage, and the straightforward relationship between better health measures and greater life span extension in shorter-lived mammals like mice or rats. What is does indicate is that some of the differences in metabolism between mammals species are very significant when it comes to life span: one hypothesis is that some of the beneficial metabolic changes brought about in mice by calorie restriction are essentially already running by default in your average human, and account for our present longevity in comparison to similarly sized mammals.

So from the perspective of a dispassionate observer of metabolic science, calorie restriction continues to offer a tremendous and ever-deepening opportunity to really dig into the operation and evolution of mammalian biochemistry. From the perspective of those of us who want to live very much longer than our predecessors, calorie restriction has to be nothing more than a common sense health practice, akin to flossing and exercise, but not something that we hang unrealistic hopes on. Real progress in living longer must come from medical science, from efforts to build rejuvenation biotechnologies that can repair the damage that causes aging. Absent advances in longevity medicine we will age and die just like our ancestors, no matter what we eat; taking care of our health is, like supporting research initiatives in longevity science, one more optimization to help us live long enough to see the deployment of therapies to treat and reverse aging.

Suitable genetic engineering of telomerase can extend life in mice, but it isn't a straightforward process, and it is unclear as to how this would translate to humans given the complex relationship between telomere biology and aging on the one hand and the differences between humans and mice on the other: "The absence of telomerase [and consequent] telomere shortening in somatic cells plays a controversial role in mammalian aging. On the one hand, genetic knockout of telomerase function in mice has little noticeable effect on the aging of first-generation mutants. Serious phenotypic consequences are seen only in the fourth through sixth generations of such mutants when premature aging-associated phenotypes appear. This is because the normal length of mouse telomeres is sufficient for several mouse life spans, including all of the cell divisions associated with development. On the other hand, ectopic expression of the catalytic subunit of telomerase (telomerase reverse transcriptase, TERT) in epithelial cells has been reported to extend life span by up to 40% in mice engineered to be cancer-resistant. Unfortunately, ectopic expression of TERT in wild-type mice or mutations in human TERT increase cancer risk. There is evidence that active telomerase [and consequently] long telomeres protect cells from the metabolic and mitochondrial compromise that occurs when shortened telomeres induce p53 ... Ironically, shortened telomeres also result in increased cancer rates, probably due to increased genomic instability. Consistent with a homeostatic mechanism is the observation that telomerase reactivation has been shown to partially reverse tissue degeneration in aged telomerase-deficient mice (fourth generation). There is a paradox here: Mouse chromosomes possess enough reserve telomere length to fuel cell divisions for up to six organismal generations, yet mice apparently have at least a subset of cells in which dysfunction is linked to shorter telomeres and/or the absence of telomerase within a single life span. This paradox relates to the critical question of whether sufficient clinical benefit could result from ectopic telomerase expression in human aging and in diseases associated with shortened telomeres ... Of course, one potentially important difference is that humans have significantly shorter telomeres than mice."

Link: http://online.liebertpub.com/doi/full/10.1089/rej.2012.1359

A short article on longevity science than manages to miss most of the interesting work presently taking place by focusing on the mainstream of metabolic manipulation to slow aging and researchers who talk about compression of morbidity without extending life: "As scientists make new breakthroughs in understanding the mechanics of aging, the upper limits of aging might be changing for Homo sapiens. Already, life expectancy has increased dramatically since the late nineteenth century, when it was 40 for males and 42 for females at birth, and age 58 and 59 respectively if they survived to age 10 (infant mortality was much higher in 1890). Life expectancy is expected to keep rising to perhaps age 100 sometime in the 22nd century, according to the United Nations. This comes from better hygiene and nutrition, and also from bio-med breakthroughs that range from antibiotics to targeted therapies for cancer and robotic surgery. Is it possible that new waves of discoveries might take us on a path of even more dramatic increases in life extension? Until recently, mainstream scientists would have answered with an emphatic no, suggesting that this was a fantasy offered up by alchemists, charlatans, and pseudo-scientists. Two trends have shifted this point of view. The first is a realization that aging is one of the greatest risk factors for many diseases, and therefore needs to be seriously addressed by biomedical researchers. Not with a primary endpoint of radically prolonging life, which remains controversial, but as a major element of conventional research into understanding and combating cancer, diabetes, heart disease, and other chronic diseases of the elderly. The second trend is that scientists have succeeded in upping the lifespan of many animals, sometimes dramatically, discoveries that have launched wide-ranging research into the mechanics of aging. The big question is: Can these processes be replicated in humans?"

Link: http://www.theatlantic.com/health/archive/2012/08/when-im-164-how-can-bioscience-push-the-limits-of-lifespan/261814/