The development of artificial replacements proceeds in parallel with tissue engineering as a way to build replacement parts for damaged corneas. Here, publicity materials tout recent progress in artificial corneas:

ArtCornea is based on a polymer with high water-absorbent properties. [Researchers] have added a new surface coating to ensure anchorage in host tissue and functionality of the optic. The haptic edge was chemically altered to encourage local cell growth. These cells graft to the surrounding human tissue, which is essential for anchorage of the device in the host tissue. The researchers aimed to enlarge the optical surface area of the implant in order to improve light penetration beyond what had previously been possible ... Once ArtCornea is in place, it is hardly visible, except perhaps for a few stitches. It's also easy to implant and doesn't provoke any immune response

The specialists have also managed to make a chemically and biologically inert base material biologically compatible for the second artificial cornea, ACTO-TexKpro. [They] achieved this by selectively altering the base material, polyvinylidene difluoride, by coating the fluoride synthetic tissue with a reactive molecule. This allows the patient's cornea to bond together naturally with the edge of the implant, while the implant's inner optics, made of silicon, remain free of cells and clear. The ACTO-TexKpro is particularly suitable as a preliminary treatment, for instance if the cornea has been destroyed as a consequence of chronic inflammation, a serious accident, corrosion or burns.

TexKpro and ArtCornea [were] first tested by the doctors in the [laboratory] in vivo in several rabbits. After a six month healing process, the implanted prostheses were accepted by the rabbits without irritation, clearly and securely anchored within the eye. Tests carried out following the operation showed that the animals tolerated the artificial cornea well. [Clinical trials will] soon commence at the Eye Clinic Cologne-Merheim.

Link: http://www.fraunhofer.de/en/press/research-news/2012/october/artificial-cornea-gives-the-gift-of-vision.html

Source:
http://www.fightaging.org/archives/2012/10/noting-progress-in-artificial-cornea-development.php

Here is a recently posted video in which SENS Foundation cofounder Aubrey de Grey discusses the mechanisms of aging and what to do about them:

Aubrey de Grey is a well-known researcher on the process of ageing.
He sees ageing as a disease and believes science will soon be able to slow it down so that we'll have more time for science to advance even further so we can fix the cellular damages of ageing and - maybe one day - live forever.

"Live forever" is such a clumsy shortage for agelessness achieved through medical technology, given that you'd have to put in a lot of work to push much past a few thousand years in a human body - even with a risk function for fatal accidents that is small compared to the present day. But you can't exactly stop people from using the phrase.

The video above was published by Basil Gelpke, who is also behind Human 2.0, a DVD release that examines the prospects for engineered longevity, among other topics of interest to transhumanists. It's subtitled in German, but is English language:

The human being will be the first species able to understand its own blueprint. The rapidly increasing knowledge of genetics, nanotechnology, robotics, and AI will dwarf everything philosophers, scientists, science fiction writers and other visionaries have ever conceived. Human life without disease and possibly even without death doesn't seem impossible anymore.

Source:
http://www.fightaging.org/archives/2012/10/aubrey-de-grey-on-longevity-science.php

One of the handful of genetic alterations shown to extend life in mice is removal of adenylyl cyclase 5 (AC5). Researchers have noted in the past that this seems to share mechanisms with the longevity induced by calorie restriction - indeed, it is suspected that many of the varied known ways of altering laboratory animals to extend healthy life are in fact different methods to activate the same few base changes in metabolism. Here is another paper on this topic:

Adenylyl cyclase type 5 knockout mice (AC5 KO) live longer and are stress resistant, similar to calorie restriction (CR). AC5 KO mice eat more, but actually weigh less and accumulate less fat compared to [wild type] mice. CR applied to AC5 KO result in rapid decrease in body weight, metabolic deterioration and death. These data suggest that despite restricted food intake in CR, but augmented food intake in AC5 KO, the two models affect longevity and metabolism similarly.

To determine shared molecular mechanisms, mRNA expression was examined genome-wide for brain, heart, skeletal muscle and liver. Significantly more genes were regulated commonly rather than oppositely in all the tissues in both models, indicating commonality between AC5 KO and CR.

Gene Ontology analysis identified many significantly regulated, tissue-specific pathways shared by the two models, including sensory perception in heart and brain, muscle function in skeletal muscle, and lipid metabolism in liver. Moreover, when comparing gene expression changes in the heart under stress, the glutathione regulatory pathway was consistently upregulated in the longevity models but downregulated with stress. In addition, AC5 and CR shared changes in genes and proteins involved in the regulation of longevity and stress resistance, including Sirt1, ApoD and olfactory receptors in both young and intermediate age mice. Thus, the similarly regulated genes and pathways in AC5 KO and CR [suggest] a unified theory for longevity and stress resistance.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23020244

Source:
http://www.fightaging.org/archives/2012/10/shared-mechanisms-for-longevity-via-calorie-restriction-and-ac5-knockout.php

Wired is running a photo essay on cryonics, the low-temperature preservation technique that intends to preserve the structure of the mind sufficiently well for patients to be restored to life by future technology:

The Prospect of Immortality is a six-year study by UK photographer Murray Ballard, who has traveled the world pulling back the curtain on the amateurs, optimists, businesses and apparatuses of cryonics.

"It's not a large industry," says Ballard, who visited the Alcor Life Extension Foundation in Phoenix, Arizona; the Cryonics Institute in Detroit, Michigan; KrioRus in Moscow, Russia; and Suspended Animation Inc in Boytan Beach, Florida; among others.

Cryonics is the preservation of deceased humans in liquid nitrogen at temperatures just shy of its boiling point of -196°C/77 Kelvin. Cryopreservation of humans is not reversible with current science, but cryonicists hypothesize that people who are considered dead by current medical definitions may someday be recovered by using advanced future technologies.

Stats are hard to come by, but it is estimated there are about 2,000 people signed up for cryonics and approximately 250 people currently cryopreserved. Over 100 pets have also been placed in vats of liquid nitrogen with the hopes of a future recovery.

Link: http://www.wired.com/rawfile/2012/10/murray-ballard-cyronics/

Source:
http://www.fightaging.org/archives/2012/10/a-cryonics-photo-essay-at-wired.php

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/

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

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.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

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-?-oxidation-related genes extended median and maximum lifespan [in flies] and increased stress resistance, suggesting that the level of fatty-acid ?-oxidation regulates lifespan.

Consistent with our results, many investigations have suggested fatty-acid ?-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 ?-oxidation. In addition, enigma mutant, which exhibits oxidative stress resistance and a longevity phenotype, was found to encode a fatty-acid-?-oxidation related enzyme. ... However, the present study is the first to provide direct evidence that the modulation of fatty-acid-?-oxidation components extends lifespan.

Our data showed that lifespan extension by dietary restriction decreased with the overexpression of fatty-acid ?-oxidation-related genes, indicating that lifespan extension by fatty-acid-?-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/

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

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.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

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

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

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

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

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.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

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

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

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 A? peptides induce mitochondrial dysfunction, oxidative stress, and alterations in the metabolic phenotype of astrocytes; we examined whether A? peptides initiate the senescence response in these cells. In vitro, we found that exposure of astrocytes to A?1-42 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.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

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/

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

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

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

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.

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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

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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/

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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.

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