Fight Aging!

Some publicity materials are presently doing the (late) rounds for a January review of progress in tissue engineering over the course of 2012. The review paper is open access, so I'm assuming that this is the standard process of picking a paper at some point after it is published and allowing open access for a while to draw some attention to the journal in question. Still, it's an interesting read, providing a perspective from inside the field on what is actually important enough to mention.

The merging of tissue engineering and regenerative medicine (TERM) forms an enormously broad, energetic, and important field of medical research. Not a week goes by without something new and vital happening in a regenerative medicine laboratory somewhere in the world, and vast sums of money flow into advancing the state of the art. Arbitrary tissues and organ structures grown from a patient's own cells are not so far ahead in the future now, and neither are ways to coerce the body to rebuild itself from the inside out. There is a certainly a sense of excitement among those involved.

Tissue Engineering and Regenerative Medicine: Recent Innovations and the Transition to Translation

The first challenge in conducting this review was the sheer number of recent publications in the TERM field. [The] number of TERM articles continues to rise with nearly 4000 original articles published in 2010, compared to a mere 360 a decade earlier. This can be partially attributed to the increasing use of the same common terminology, particularly for the more recent "regenerative medicine." Still, there is no doubt that our field is expanding and capturing a larger portion of the work done across the biomedical sciences.

Many seemingly discordant lines of research have now become intertwined in TERM and constitute the fabric of our field, with these concepts arising from the blurring of boundaries between traditional disciplines. While this point is sometimes easy to forget, much of what we now consider commonplace in TERM was only a short time ago separated by barriers of dogma and discipline. As these lines continue to blur, and multi-disciplinary research becomes more the rule than the exception, our field is experiencing tremendous growth.

The pace of growth is now so fast that it impossible for most of us to keep up with the field as a whole, or even a small subset of it. For example, a TERM search specific to "cartilage" returns more than 450 articles published in 2011 alone, meaning that one would need to read more than one article per day just to stay abreast of this small portion of the TERM terrain.

We found considerable innovation in a number of traditional TERM fields, but also new ideas that are beginning to take hold in emerging focal areas. For instance, in the realm of tissue replacement, we are now seeing not just scaffolds of ever-increasing complexity derived from standard engineering methods, but also complex scaffolds predicated on natural designs (and native tissues themselves, once decellularized). In the broader field of regenerative medicine, we are seeing developmental biology begin to address not just the formation of tissues, but the specific role that endogenous stem cells play in both generative and regenerative processes. Integrating these basic science findings with novel materials that specifically recruit endogenous populations may provide a next wave in smart biomaterials for tissue repair. Likewise, new cell sources, most prominently iPSCs, have come to the fore, making autologous cell-based therapies for any tissue a real possibility.

Finally, our objective screen showed that ours is truly a translational field, and that TERM advances are being reduced to clinical practice at an ever-increasing rate. [Both] the quantitative nature of these outcome measures and levels of evidence in support of these applications are advancing as well. Together, these advances are now beginning to change the lives of small subsets of the population, and in the future, these novel approaches will be able to address a host of diseases and instances of tissue degeneration that were heretofore untreatable.

Metformin, used as a treatment for diabetes, is a weak candidate for a calorie restriction mimetic drug, one that causes some of the same metabolic changes (and thus hopefully health and longevity benefits) as calorie restriction. The evidence for health and longevity benefits actually resulting from this usage is mixed and debatable, however; certainly nowhere near as clear as for, say, rapamycin. Here researchers propose that metfomin's method of action stems in part from suppressing chronic inflammation, which is known to contribute to the progression of age-related frailty and disease:

[Researchers] found that the antidiabetic drug metformin reduces the production of inflammatory cytokines that normally activate the immune system, but if overproduced can lead to pathological inflammation, a condition that both damages tissues in aging and favors tumor growth. Cells normally secrete these inflammatory cytokines when they need to mount an immune response to infection, but chronic production of these same cytokines can also cause cells to age. Such chronic inflammation can be induced, for example by smoking, and old cells are particular proficient at making and releasing cytokines.

"We were surprised by our finding that metformin could prevent the production of inflammatory cytokines by old cells. The genes that code for cytokines are normal, but a protein that normally triggers their activation called NF-kB can't reach them in the cell nucleus in metformin treated cells. We also found that metformin does not exert its effects through a pathway commonly thought to mediate its antidiabetic effects. We have suspected that metformin acts in different ways on different pathways to cause effects on aging and cancer. Our studies now point to one mechanism."

Link: http://www.sciencedaily.com/releases/2013/03/130327093604.htm

All commonalities in cancer are interesting, as part of the high cost of dealing with cancer is based on the many, many different varieties and the great variability of its biochemistry even between individual tumors. Anything that is common between many types of cancer and between tumors offers a possibility of a lower-cost and broader therapy. The cell surface marker CD47 has shown up of late as a possible commonality, and work continues to see whether a therapy can be built on this:

A decade ago, [researchers] discovered that leukemia cells produce higher levels of a protein called CD47 than do healthy cells. CD47 [is] also displayed on healthy blood cells; it's a marker that blocks the immune system from destroying them as they circulate. Cancers take advantage of this flag to trick the immune system into ignoring them. In the past few years, [researchers] showed that blocking CD47 with an antibody cured some cases of lymphomas and leukemias in mice by stimulating the immune system to recognize the cancer cells as invaders. Now, [researchers] have shown that the CD47-blocking antibody may have a far wider impact than just blood cancers.

"What we've shown is that CD47 isn't just important on leukemias and lymphomas. It's on every single human primary tumor that we tested." Moreover, [the scientists] found that cancer cells always had higher levels of CD47 than did healthy cells. How much CD47 a tumor made could predict the survival odds of a patient. To determine whether [targeting] CD47 was beneficial, the scientists exposed tumor cells to macrophages, a type of immune cell, and anti-CD47 molecules in petri dishes. Without the drug, the macrophages ignored the cancerous cells. But when the CD47 was [targeted], the macrophages engulfed and destroyed cancer cells from all tumor types.

Next, the team transplanted human tumors into the feet of mice, where tumors can be easily monitored. When they treated the rodents with anti-CD47, the tumors shrank and did not spread to the rest of the body. In mice given human bladder cancer tumors, for example, 10 of 10 untreated mice had cancer that spread to their lymph nodes. Only one of 10 mice treated with anti-CD47 had a lymph node with signs of cancer. Moreover, the implanted tumor often got smaller after treatment - colon cancers transplanted into the mice shrank to less than one-third of their original size, on average.

Link: http://news.sciencemag.org/sciencenow/2012/03/one-drug-to-shrink-all-tumors.html

Why do I vocally support rejuvenation research based on the Strategies for Engineered Negligible Senescence (SENS) over other forms of longevity science? Why do I hold the view that SENS and SENS-like research should be prioritized and massively funded? The short answer to this question is that SENS-derived medical biotechnology has a much greater expected utility - it will most likely produce far better outcomes, and at a lower cost - than other presently ongoing lines of research into creating greater human longevity.

What is SENS?

But firstly, what is SENS? It is more an umbrella collection of categories than a specific program, though it is the case that narrowly focused SENS research initiatives run under the auspices of the SENS Research Foundation. On the science side of the house, SENS is a synthesis of existing knowledge from the broad mainstream position regarding aging and the diseases of aging: that aging is caused by a stochastic accumulation of damage at the level of cells and protein machinery in and around these cells. SENS is a proposal, based on recent decades of research, as to which of the identified forms of damage and change in old tissues are fundamental - i.e. which are direct byproducts of metabolic operation rather than cascading effects of other fundamental damage. On the development side of the house, SENS pulls together work from many subfields of medical research to show that there are clear and well-defined ways to produce therapies that can repair, reverse, or make irrelevant these fundamental forms of biological damage associated with aging.

(You can read about the various forms of low-level damage that cause aging at the SENS Research Foundation website and elsewhere. This list includes: mitochondrial DNA mutations; buildup of resilient waste products inside and around cells; growing numbers of senescent and other malfunctioning cells; loss of stem cells; and a few others).

Present arguments within the mainstream of aging research are largely over the relative importance of damage type A versus damage type B, and how exactly the extremely complex interaction of damage with metabolism progresses - but not what that damage actually is. A large fraction of modern funding for aging research goes towards building a greater understanding this progression; certainly more than goes towards actually doing anything about it. Here is the thing, however: while understanding the dynamics of damage in aging is very much a work in progress, the damage itself is well known. The research community can accurately enumerate the differences between old tissue and young tissue, or an old cell and a young cell - and it has been a good number of years since anything new was added to that list.

If you can repair the cellular damage that causes aging, it doesn't matter how it happens or how it affects the organism when it's there. This is the important realization for SENS - that much of the ongoing work of the aging research community is largely irrelevant if the goal is to get to human rejuvenation as rapidly as possible. Enough is already known of the likely causes of aging to have a reasonable expectation of being able to produce laboratory demonstrations of rejuvenation in animal models within a decade or two, given large-scale funding.

Comparing Expected Values

Expected value drives human endeavor. What path ahead do we expect to produce the greatest gain? In longevity science the investment is concretely measured in money and time, and we might think of the expected value in terms of years of healthy life added by the resulting therapies. The cost of these therapies really isn't much of a factor - all major medical procedures and other therapies tend to converge to similar costs over time, based on their category: consider a surgery versus an infusion versus a course of pills, for example, where it's fairly obvious that the pricing derives from how much skilled labor is involved and how much care the patient requires as a direct result of the process.

On the input side, there are estimates for the cost in time and money to implement SENS therapies for laboratory mice. For the sake of keeping things simple, I'll note that these oscillate around the figures of a billion dollars and ten years for the crash program of fully-funded research. A billion dollars is about the yearly budget of the NIA these days, give or take, which might be a third of all research funding directed towards aging - by some estimates, anyway, though this is a very hard figure to verify in any way. It's by no means certain the that the general one third/two thirds split between government and private research funding extends to aging research.

On the output side, early SENS implementations would be expected to take an old mouse and double its remaining life expectancy - e.g. produce actual rejuvenation, actual repair and reversal of the low-level damage that causes aging, with repeated applications at intervals producing diminishing but still measurable further gains. This is the thing about a rejuvenation therapy that works; you can keep on applying it to sweep up newly accruing damage.

So what other longevity science do we have to compare against? The only large running programs are those that have grown out of the search for calorie restriction mimetic drugs. So there is the past decade or so of research into surtuins, and there is growing interest in mTOR and rapamycin analogs that looks to be more of the same, but slightly better (though that is a low bar to clear).

In the case of sirtuins, money has certainly flowed. Sirtris itself sold for ~$700 million, and it's probably not unreasonable to suggest that a billion dollars has gone into broader sirtuin-related research and development over the past decade. What does the research community have to show for that? Basically nothing other than an increased understanding of some aspects of metabolism relating to calorie restriction and other adaptations that alter life span in response to environmental circumstances. Certainly no mice living longer in widely replicated studies as is the case for mTOR and rapamycin - the sirtuin results and underlying science are still much debated, much in dispute.

The historical ratio of dollars to results for any sort of way to manipulate our metabolism to slow aging is exceedingly poor. The thing is, this ratio shouldn't be expected to get all that much better. Even if marvelously successful, the best possible realistic end result of a drug that slows aging based on what is known today - say something that extracts the best side of mTOR manipulation with none of the side-effects of rapamycin - is a very modest gain in human longevity. It can't greatly repair or reverse existing damage, it can't much help those who are already old become less damaged, it will likely not even be as effective as actual, old-fashioned calorie restriction. The current consensus is that calorie restriction itself is not going to add more than a few years to a human life - though it certainly has impressive health benefits.

(A sidebar: we can hope that one thing that ultimately emerges from all this research is an explanation as to how humans can enjoy such large health benefits from calorie restriction, commensurate with those seen in animals such as mice, without also gaining longer lives to match. But if just eating fewer calories while obtaining good nutrition could make humans reliably live 40% longer, I think that would have been noted at some point in the last few thousand years, or at least certainly in the last few hundred).

From this perspective, traditional drug research turned into longevity science looks like a long, slow slog to nowhere. It keeps people working, but to what end? Not producing significant results in extending human longevity, that's for sure.

Ergo...

The cost of demonstrating that SENS is the right path or the wrong path - i.e. that aging is simply an accumulation of damage, and the many disparate research results making up the SENS vision are largely correct about which forms of change in aged tissue are the fundamental forms of damage that cause aging - is tiny compared to the cost of trying to safely eke out modest reductions in the pace of aging by manipulating metabolism via sirtuins or mTOR.

The end result of implementing SENS is true rejuvenation if aging is caused by damage: actual repair, actual reversal of aging. The end result of spending the same money and time on trying to manipulate metabolism to slow aging can already be observed in sirtuin research, and can reasonably be expected to be much the same the next time around the block with mTOR - it produces new knowledge and little else of concrete use, and even when it does eventually produce a drug candidate, it will likely be the case that you could do better yourself by simply practicing calorie restriction.

The expectation value of SENS is much greater than that of trying to slow aging via the traditional drug discovery and development industry. Ergo the research and development community should be implementing SENS. It conforms to the consensus position on what causes aging, it costs far less than all other proposed interventions into the aging process, and the potential payoff is much greater.

An interesting piece on the use of scaffold materials to guide regrowth in regenerative medicine:

A research group [is] weaving nanoscale nerve-guide scaffolds from a mixture of natural chitosan and an industrial polyester polymer, using a process called electrospinning. The raw materials are dissolved in solvents and placed into a syringe, the needle of which is attached to a high-voltage supply. Charged liquid is then expelled from the needle towards an earthed collector plate. Like a spark between a cloud and a lightning conductor, the liquid stretches out to the collector, and the molecules within it form into a solid but incredibly thin thread.

The resulting minuscule fibres accrete into a dense mesh whose texture is similar to that of the body's own connective tissue. In laboratory tests, prototype nerve guides built from this nanomaterial sustained the growth of new neural cells, produced no immune reactions and were much stronger and more flexible than commercial collagen tubes. By adjusting the electrospinning process, the orientation of the nanofibres can be controlled to build scaffolds suitable for cultivating cells that need precise alignment, such as elongated muscle fibres and heart tissue.

Link: http://www.economist.com/news/technology-quarterly/21573056-biomedical-technology-tiny-forms-scaffolding-combining-biological-and-synthetic

People age at different paces: accumulating damage, dysfunction, and age-related disease comes earlier and faster for some. The current consensus is that some of that is genetic, some epigenetic, but (absent serious genetic abnormalities) most of the difference is due to commonplace lifestyle choices such as smoking, exercise, and calorie intake.

[Researchers have] found new evidence that links faster 'biological' ageing to the risk of developing several age-related diseases - including heart disease, multiple sclerosis and various cancers. "Although heart disease and cancers are more common as one gets older, not everyone gets them - and some people get them at an earlier age. It has been suspected that the occurrence of these diseases may in part be related to some people 'biologically' ageing more quickly than others."

The research team measured telomere lengths in over 48,000 individuals and looked at their DNA and identified seven genetic variants that were associated with telomere length. They then asked the question whether these genetic variants also affected risk of various diseases. As DNA cannot be changed by lifestyle or environmental factors, an association of these genetic variants which affect telomere length with a disease also would suggest a causal link between telomere length and that disease.

"These are really exciting findings. We had previous evidence that shorter telomere lengths are associated with increased risk of coronary artery disease but were not sure whether this association was causal or not. This research strongly suggests that biological ageing plays an important role in causing coronary artery disease, the commonest cause of death in the world. This provides a novel way of looking at the disease and at least partly explains why some patients develop it early and others don't develop it at all even if they carry other risk factors."

Link: http://www.sciencedaily.com/releases/2013/03/130327133339.htm

How much of age-related degeneration stems from lifestyle (secondary aging) versus inherent processes derived from the operation of metabolism (primary aging)? If you become sedentary with age, or pile on the visceral fat, then both of those are going to harm you in ways that overlap with the inherent mechanisms of aging - accelerating the accumulation of damage and dysfunction in and between the cells of your tissues.

The balance of primary versus secondary aging is likely to be different in different tissues. I noticed a few recent papers that look at narrow aspects of muscle aging and find a surprising lack of primary aging, for example. This suggests that many of the observed changes that occur in muscle early in the aging process are driven as much by a lack of exercise - and related matters of lifestyle that have a negative impact on health - as by the known forms of biological damage down at the level of cells and tissues.

Active muscle regeneration following eccentric contraction-induced injury is similar between healthy young and older adults

Repair of skeletal muscle after injury is a key aspect of maintaining proper musculoskeletal function. Studies have suggested that regenerative processes - including myogenesis and angiogenesis - are impaired during advanced age, but evidence from humans is limited. This study aimed to compare active muscle regeneration between healthy young and older adults. We evaluated changes [in] muscle regeneration at precisely two (T2) and seven (T3) days following acute muscle injury [in] men and women aged 18-30 and ≥ 70 years, matched for gender and body mass index.

Following muscle injury, force production declined 16% and 14% in young and older adults, respectively, by T2 and in each group returned to 93% of baseline strength by T3. Despite modest differences in the pattern of response, post-injury changes in intramuscular concentrations of myogenic growth factors and number of myonuclear cells were largely similar between groups. Likewise, post-injury changes [in] indices of inflammation [and] angiogenesis did not significantly differ between groups. These findings suggest that declines in physical activity and increased co-morbidity may contribute to age-related impairments in active muscle regeneration rather than aging per se.

The muscle protein synthetic response to the combined ingestion of protein and carbohydrate is not impaired in healthy older men

Aging is associated with a progressive decline in skeletal muscle mass. It has been hypothesized that an attenuated muscle protein synthetic response to the main anabolic stimuli may contribute to the age-related loss of muscle tissue. The aim of the present study was to compare the muscle protein synthetic response following ingestion of a meal-like amount of dietary protein plus carbohydrate between healthy young and older men.

Twelve young (21 ± 1 years) and 12 older (75 ± 1 years) men [consumed labeled protein, allowing] us to assess the subsequent incorporation of casein-derived amino acids into muscle protein. [There were] no differences between groups. We conclude that the use of dietary protein-derived amino acids for muscle protein synthesis is not impaired in healthy older men following intake of protein plus carbohydrate.

You can't exercise your way out of aging to death, but you can certainly make life harder for yourself (and shorter, and more expensive) by failing to remain trim and fit. On the flip side of the coin, there is this recent research below: it suggests that the intrinsic primary aging of muscle isn't something that you can do much about through exercise, even while exercise is enormously beneficial for other reasons.

Molecular Networks of Human Muscle Adaptation to Exercise and Age

A fundamental challenge for modern medicine is to generate new strategies to cope with the rising proportion of older people within society, as unaddressed it will make many health care systems financially unviable. Ageing impacts both quality of life and longevity through reduced musculoskeletal function. What is unknown in humans is whether the decline with age, referred to as "sarcopenia," represents a molecular ageing process or whether it is primarily driven by alterations in lifestyle, e.g. reduced physical activity and poor nutrition.

Because the details of such interactions will be uniquely human, we aimed to produce the first reproducible global molecular profile of human muscle age, one that could be validated across independent clinical cohorts to ensure its general applicability. We combined this analysis with extensive data on the impact of exercise training on human muscle phenotype to then identify the processes predominately associated with age and not environment.

We were able to identify unique gene pathways associated with human muscle growth and age and were able to conclude that human muscle age-related molecular processes appear distinct from the processes directly regulated by those of physical activity.

This sort of regenerative medicine research will in the long term help to decipher the signaling produced by different sorts of stem cells in different tissues. Researchers will ultimately remove the need for cell transplants to boost regenerative capabilities and rebuild damaged organs, and produce these effects by controlling existing cell populations:

Amniotic fluid stem (AFS) cells were harvested from rodent amniotic fluid and given to rats with necrotizing enterocolitis (NEC). Other rats with the same condition were given bone marrow stem cells taken from their femurs, or fed as normal with no treatment, to compare the clinical outcomes of different treatments. NEC-affected rats injected with AFS cells showed significantly higher survival rates a week after being treated, compared to the other two groups. Inspection of their intestines, including with micro magnetic resonance imaging (MRI), showed the inflammation to be significantly reduced, with fewer dead cells, greater self-renewal of the gut tissue and better overall intestinal function.

While bone marrow stem cells have been known to help reverse colonic damage in irritable bowel disease by regenerating tissue, the beneficial effects from stem cell therapy in NEC appear to work via a different mechanism. Following their injection into the gut, the AFS cells moved into the intestinal villi - the small, finger-like projections that protrude from the lining of the intestinal wall and pass nutrients from the intestine into the blood. However, rather than directly repairing the damaged tissue, the AFS cells appear to have released specific growth factors that acted on progenitor cells in the gut which in turn, reduced the inflammation and triggered the formation of new villi and other tissues.

"Stem cells are well known to have anti-inflammatory effects, but this is the first time we have shown that amniotic fluid stem cells can repair damage in the intestines. [Although] amniotic fluid stem cells have a more limited capacity to develop into different cell types than those from the embryo, they nevertheless show promise for many parts of the body including the liver, muscle and nervous system."

Link: http://www.eurekalert.org/pub_releases/2013-03/ucl-afs032213.php

A modest step forward on the path towards tissue engineered ovaries:

A proof-of-concept study suggests the possibility of engineering artificial ovaries in the lab to provide a more natural option for hormone replacement therapy for women. [Researchers] report that in the laboratory setting, engineered ovaries showed sustained release of the sex hormones estrogen and progesterone.

The project to engineer a bioartificial ovary involves encapsulating ovarian cells inside a thin membrane that allows oxygen and nutrients to enter the capsule, but would prevent the patient from rejecting the cells. With this scenario, functional ovarian tissue from donors could be used to engineer bioartificial ovaries for women with non-functioning ovaries.

[Researchers] isolated the two types of endocrine cells found in ovaries (theca and granulosa) from 21-day-old rats. The cells were encapsulated inside materials that are compatible with the body. The scientists evaluated three different ways of arranging the cells inside the capsules. The function of the capsules was then evaluated in the lab by exposing them to follicle-stimulating hormone and luteinizing hormone, two hormones that stimulate ovaries to produce sex hormones. The arrangement of cells that most closely mimicked the natural ovary (layers of cells in a 3-D shape) secreted levels of estrogen that were 10 times higher than other cell arrangements.

The capsules also secreted progesterone as well as inhibin and activin, two hormones that interact with the pituitary and hypothalamus and are important to the body's natural system to regulate the production of female sex hormones. "Cells in the multilayer capsules were observed to function in similar fashion to the native ovaries. The secretion of inhibin and activin secretion suggests that these structures could potentially function as an artificial ovary by synchronizing with the body's innate control system."

Link: http://www.eurekalert.org/pub_releases/2013-03/wfbm-rbf032613.php

Today, we ponder the use of words, as is the fate of all those who reach the end of a day without the energy remaining to do something that is actually useful. "Deathism" and "deathist" are neologisms still in that fuzzy state of settling to a final dictionary meaning - should they ever accrue the sort of usage that leads to notice by the lexical powers that be. When I say deathism, I mean a point of view or philosophy that promotes death. In the context of Fight Aging!, that almost always means death by aging: deathist views are those of technological relinquishment, apologism for degenerative aging, and shying away from the medical progress that could eliminate the death and suffering caused by aging. A deathist individual is one who advocates or adheres to one of these worldviews, with modern Malthusian environmentalism (an ofttimes disturbing outgrowth of the civic religion) and traditional religious cultures being the largest communities.

There is, however, a certain dismissiveness and scorn that can soak into short *-ist terms. "Oh, you support X, you're just another Xist!" The world is full of dumb arguments, knee-jerk rationalizations, and heads stuck in the sand when it comes to aging and the potential future of rejuvenation biotechnology. It is enormously frustrating to live in the madhouse, among the lemming herd babbling as they head for the cliff, at the bottom of the pit of nihilism, in the city of suicidal barbarians - but not everyone who fails to rally to the cause is just another deathist, either figuratively or literally. There are always subtleties.

Would it help to call people to call more respectable aging apologists something like "death advocates" instead? I've no idea. Some of their viewpoints are entirely legitimate, in that they actually want to age and die, and are explaining why. Others are far less so, in that these talking heads have no problem in advocating for states to use force to block the development of ways to reverse aging. That's something I have a hard time treating with any respect; it's actually far, far worse than any plausible modern war or the other equally terrible things that people conspire to do to one another in the name of government. A bare few days of postponement of the advent of rejuvenation biotechnology costs more lives than US military adventures of the past decade or so. Two years of postponement tops the highest estimated death toll for the Second World War. The current regulatory structure imposed by the US Food and Drug Administration (FDA) can easily accumulate decades of postponement of new medical technologies over successive business and development cycles. For the greatest crimes of governance, one only has to look to medical regulation.

In any case, back to deathism; this meandering post was prompted by a short piece over at the Rational Argumentor:

Who Are the True "Deathists"

My view on this matter is a nuanced one. It is crucial to make a distinction between (i) people who simply hold the common "tragic worldview" - who accept their mortality as inevitable and try to "make peace" with it and (ii) people who actively work to stop life-extension technologies. The former are simply mistaken and can be reasoned with, persuaded, or at least led to gradually become more comfortable with life extension as it becomes ever more real. The latter, however, might not be open to persuasion and might pursue legislative action (or worse) to stop life-extension research. Every person's arguments should be addressed civilly and intelligently.

The label "deathist" is not uncivil per se, however, and has its place with regard to people who cannot be swayed by argument or evidence from a position that is actively hostile to life extension. [Calling] these people "deathists" is not aimed at persuading them, but rather at alerting possibly more objective third parties of the dangers of their views. If there is still the opportunity to persuade someone, then labels of this sort should not be directed at that person.

There are all too few life and death matters in this modern world of technology and comfort. The one we all touch on, and which will most greatly affect us all, is the pace of progress towards biotechnologies that can repair and reverse aging. It is the most important line item of the day, and the one most ignored in comparison to its importance.

Autophagy is the collection of housekeeping processes that aim to keep a cell in good shape - free from damaged components and unwanted metabolic byproducts. More autophagy is a good thing, and boosted levels of autophagy seem to be involved in many of the methods found to extend life in laboratory animals.

By way of following up on a post from yesterday on apparent damage repair and reversal of some markers of aging in induced pluripotent stem cells (iPSCs), I thought I'd direct your attention to a recent open access paper on the involvement of autophagy in stem cell biology. Perhaps much of the seeming cellular rejuvenation brought about through passing old cell lineages through an induced pluripotent stage has to do with greatly enhanced autophagy:

The implication of autophagy in the maintenance of stemness adds a new layer of control on stem cell activity. Firstly, autophagy may serve as a critical mechanism for the regulation of self-renewal and differentiation. Indeed, stem cells require especially efficient protein turnover to eliminate unwanted proteins, which may otherwise accumulate and impair identity and function. Both autophagy and the ubiquitin-proteasome system (UPS) are important for protein quality control and the maintenance of cellular homeostasis, and they cooperate to regulate cellular aging.

Dysfunction or decrease of the stem cell pools is typical of physiological and pathological aging; it would be therefore interesting to determine how these two protein degradation pathways are coordinated in the regulation of stem cell homeostasis, and how the dysregulation of autophagy in stem cells is linked to aging and degenerative diseases. Additionally, the involvement of autophagy in somatic reprogramming suggests a new methodological basis for developing strategies to efficiently generate iPSCs. Finally, increased autophagy may enable cells to overcome the cellular senescence barrier by remodelling the cell cycle machinery or by promoting the turnover of the 'senescent' subcellular architecture.

In summary, the study of the interplay between autophagy and cell stemness will not only increase our understanding of the mechanisms and pathways through which autophagy contributes to stem cell maintenance and differentiation, but also enhance our knowledge of the roles of autophagy in human development, aging, and various degenerative diseases. Stem cell rejuvenation and function and large-scale production of high quality transplantable materials through active manipulation of autophagic pathways using small molecules and/or targeted genome-editing technology may be more than a dream.

Link: http://onlinelibrary.wiley.com/doi/10.1002/emmm.201201999/full

Every cell has its herd of bacteria-like mitochondria, generating fuel for cellular metabolism but also emitting damaging reactive compounds - largely damaging themselves, in fact. Differences in mitochondrial damage resistance are thought to be an important determinant of differences in species life span. Similarly, accumulated mitochondrial damage is most likely an in important contribution to degenerative aging in individuals - making therapies capable of repair a high priority. Here researchers dig in to the degree to which mitochondrial dysfunction appears in aging and various diseases:

Besides their cardinal role in ATP metabolism mitochondria are the main producers of endogenous oxidative radicals. These highly volatile species react with lipids, proteins and nucleic acids in their vicinity. The mitochondrial theory of aging states that an accumulation of damage to these macromolecules throughout the lifetime of an organism leads to cellular decay, loss of tissue homeostasis, and finally to death. Multiple lines of evidence have corroborated this theory and suggested that mitochondrial maintenance may be important in promoting longevity and healthy aging. Indeed, mitochondria have been implicated in most age related diseases such as neurodegeneration, cardiovascular disease and diabetes.

If mitochondrial dysfunction is causative in aging, we would expect the accelerated aging disorders to exhibit features of mitochondrial disease. To investigate this, we compiled a database of the clinical parameters seen in mitochondrial diseases, www.mitodb.com. Based on this database we developed extensive bioinformatics tools to dissect whether a disease could be characterized as mitochondrial or not. [Using] these tools we identified a number of diseases as mitochondrially associated that had not previously been considered as mitochondrial. Recently a number of [accelerated aging conditions] have been suggested to have mitochondrial dysfunction and these disorders were also identified by our tools.

With the validation of the tools we went on to investigate the mitochondrial involvement in a number of monogenic diseases. Interestingly, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis all showed a substantial mitochondrial involvement. Further, when adding the accelerated aging disorders to the database two groups of progeria appeared; one group associated with chromosomal instability and another group clustered with mitochondrial diseases. Normal aging seemed to associate closer with the mitochondrial group in the clustering algorithm but showed mixed mitochondrial and non-mitochondrial [attributes]. Taken together these findings indicate at least two separate causes of aging, one of them possibly being mitochondrial.

Link: http://impactaging.com/papers/v5/n3/full/100546.html

A cell is basically a (very complicated) self-modifying program, encoded in proteins. The same basic outline of human cellular machinery can encompasses everything from germline cells - that seem to be essentially immortal - through to the embryonic stem cells that give rise to all other lineages in the body during early development, through to the hundreds of types of specialized, differentiated cell that run the day to day operations of a living organism.

At some point in the process of creating a new individual, old cells with comparatively heavy damage loads work together to create young cells with comparatively light damage loads (the developing embryo). So there is rejuvenation hidden in there somewhere - possibly occurring in very early embryonic development, prior to the point at which a lot of tissue structure exists to be disrupted by what has to happen.

As the research community is learning to reprogram cells to look and act more like embryonic stem cells or germline cells, producing what are known as induced pluripotent stem cells (or iPS cells), we might not be terribly surprised to see what looks like rejuvenation. Some markers of age in reprogrammed cells and their offspring are removed or diminished in comparison to the cells prior to this reprogramming - though scientists are far from any sort of complete measure of all of the effects, and there are numerous different ways in which cells can be reprogrammed to become more like stem cells. Back in 2010, one group of researchers demonstrated the removal of accumulated mitochondrial damage: take skin cells, obtain induced pluripotent cells from them, then differentiate those iPS cells back into skin cells, and find that the new skin cells lack the mitochondrial damage of the old ones.

This sort of research is encouraging when it comes to the prospects for cell therapies that depend on taking cells from the patient, growing large numbers of them, and then infusing them back into the body. The returning cells are likely going to be of a better quality than those removed.

Here is a more recent example of some specific markers of age being removed from a cell lineage via the use of induced pluripotency. The researchers focused on blood-generating stem cells, reprogramming them into iPs cells, and then deriving a new lineage of these stem cells that was placed into laboratory animals to assess their function. The find that young blood-generating stem cells and old cells that go through this process are fairly similar, which suggests that it is epigenetic changes that cause observed differences between old and young blood in the wild, and that those changes are somehow smoothed out by the reprogramming process:

An epigenetic component of hematopoietic stem cell aging amenable to reprogramming into a young state

Aging of hematopoietic stem cells (HSCs) leads to several functional changes, including alterations affecting self-renewal and differentiation. While it is well established that many of the age-induced changes are intrinsic to HSCs, less is known about the stability of this state.

Here, we entertained the hypothesis that HSC aging is driven by the acquisition of permanent genetic mutations. To examine this issue at a functional level in vivo, we applied induced pluripotent stem (iPS) cell reprogramming of aged hematopoietic progenitors and allowed the resulting aged-derived iPS cells to reform [an HSC lineage]. Next, we functionally characterized iPS-derived HSCs in primary chimeras and following the transplantation of 're-differentiated' HSCs into new hosts; the gold standard to assess HSC function.

Our data demonstrate remarkably similar functional properties of iPS-derived and endogenous blastocyst-derived HSCs, despite the extensive chronological and proliferative age of the former. Our results therefore favor a model in which an underlying, but reversible, epigenetic component is a hallmark of HSC aging rather than being driven by an increased DNA mutation burden.

The engineering of replacement organs is progressing. There are ongoing successes with less functional tissue masses such as the bladder wall and trachea, but sights are set on building complex organs such as the heart:

Since a laboratory in North Carolina made a bladder in 1996, scientists have built increasingly more complex organs. There have been five windpipe replacements so far. A London researcher, Alex Seifalian, has transplanted lab-grown tear ducts and an artery into patients. He has made an artificial nose he expects to transplant later this year in a man who lost his nose to skin cancer.

Now, with the quest to build a heart, researchers are tackling the most complex organ yet. The payoff could be huge, both medically and financially, because so many people around the world are afflicted with heart disease. Researchers see a multi-billion-dollar market developing for heart parts that could repair diseased hearts and clogged arteries.

In additional to the artificial nose, Dr. Seifalian is making cardiovascular body parts. He sees a time when scientists would grow the structures needed for artery bypass procedures instead of taking a vein from another part the body. As part of a clinical trial, Dr. Seifalian plans to transplant a bioengineered coronary artery into a person later this year.

Dr. Aviles trained as a cardiologist but became frustrated with the difficulty of treating patients with advanced heart disease. [He] was approached in 2009 by a U.S. scientist, Doris Taylor, who had already grown a beating rat heart in the [lab]. Instead of using a man-made scaffold, Dr. Taylor had used the scaffolding from an actual rat heart as the starting point.

Growing a heart is much harder than, say, growing a windpipe, because the heart is so big and has several types of cells, including those that beat, those that form blood vessels, and those that help conduct electrical signals. For a long time, scientists didn't know how to make all the cells grow in the right place and in the right order.

Dr. Aviles said he hopes to have a working, lab-made version ready in five or six years, but the regulatory and safety hurdles for putting such an organ in a patient will be high. The most realistic scenario, he said, is that "in about 10 years" his lab will be transplanting heart parts. He and his team already have grown early-stage valves and patches that could be used some day to repair tissue damaged by heart attack.

Link: http://online.wsj.com/article/SB10001424127887323699704578328251335196648.html

Registration for the forthcoming SENS6 conference is now open. To get a sense of how this conference series runs and the noteworthy folk who attend, you might take a look at the recorded presentations or list of abstracts from SENS5, held in 2011:

You are cordially invited to participate in the sixth Strategies for Engineered Negligible Senescence (SENS) Conference, which will be held from 3rd - 7th September, 2013 at Queens' College, Cambridge.

The purpose of the SENS conference series, like all the SENS initiatives (such as the journal Rejuvenation Research), is to expedite the development of truly effective therapies to postpone and treat human aging by tackling it as an engineering problem: not seeking elusive and probably illusory magic bullets, but instead enumerating the accumulating molecular and cellular changes that eventually kill us and identifying ways to repair - to reverse - those changes, rather than merely to slow down their further accumulation. This broadly defined regenerative medicine - which includes the repair of living cells and extracellular material in situ - applied to damage of aging, is what we refer to as rejuvenation biotechnologies.

The meeting will comprise invited talks, short oral presentations of submitted abstracts, and poster sessions. There will be no concurrent sessions. Talks will take place in the Fitzpatrick Lecture Hall. Poster sessions will take place each evening in the conservatory adjacent to the bar. The conference will also feature the traditional punting on the Cam: an hour on the Backs for the faint-hearted, and an afternoon or evening trip to Grantchester for the rest of us.

Link: http://sens.org/outreach/conferences/sens6

Gerontocracy:

Government by a council of elders. Government by old people.

There are many knee-jerk reactions to the prospect of greatly increased healthy human life spans, most based on mistaken beliefs regarding the technologies needed, or mistaken beliefs regarding the way the world actually works - economics, human action, incentives. Some people believe that longer lives will result in stagnation, which is actually one of the more ridiculous and improbably outcomes once you start to pick it apart in any detail. Human society is restless and changeable on timescales far shorter than current lifespans, and the reasons why are rooted in day to day human nature. Our ambitions operate on a horizon of a few years, and that wouldn't change all that much were we to live for centuries. We are driven to influence the world today, now, regardless of the years that lie ahead of us. So the fashions of this year are gone by the next. The idols of popular culture rise and fall with rapidity. The political and business leaders of this decade are gone in the next, displaced by peers. Even corruption and revolution on a grand scale are usually only a matter of a few decades, not lifetimes.

Nonetheless, rationality rarely prevails in knee-jerk reactions - so folk think of stagnation, even in the midst of this boundlessly energetic society we live in, packed wall to wall with constant, ongoing change. A subset of these beliefs on human longevity and stagnation involve the nebulous fear of a future gerontocracy, the rise of a self-perpetuating ruling elite of ageless individuals. Funnily, this is often voiced by people who are, unlike myself, perfectly comfortable with today's Western governments. I say funnily because I have to ask: are not our present societies already gerontocracies? Isn't any civilized society a gerontocracy? Who has had the most time to gather connections, a network, and make good use of them? The old. Who has had the most time to gather resources and invest them? The old. Who has had to most time to become truly talented and sought after? The old. Who has had the most time to work their way through a social hierarchy to challenge its existing leaders? The old. Where then will the elite and the leaders tend to arise? From the old.

Take a look at who just runs and influences companies, governments, knitting circles, successful non-profit initiatives, extended families, and so on and so forth for every human endeavor. Young leaders exist, but they are a minority among the ranks of the old. This is the natural state of affairs for any society that possesses enough technology to make thought and craft more important than strength and vigor.

All that is terrible in our present societies lies in the growing centralization of power, not the chronological age of those eagerly engaged in furthering the road to serfdom and empire. Even as power is centralized, there is still a year by year turnover of figures - even in the most defensible and corruptly secure positions of power and influence. They are largely kicked out by some combination of their peers and the mob in the sort of political anarchy that exists at the top, above the laws made for the little people. It is the rare individual who can stick it out long enough to be removed by the infirmities of age, even now, in this age of human lives that are all too brief in comparison to what is to come.

But back to the point. We live in a gerontocracy, and so did most of our ancestors. Yet change still happens just as rapidly as in past centuries when fewer people lived into later life in the sort of good shape they can manage today. Fear of some sort of comic-book gerontocracy emerging in the future seems, frankly, somewhat silly. But here is an article on the topic that treats such fears with a little more respect than I'm inclined to deploy.

http://io9.com/will-old-people-take-over-the-world-458358266

The human lifespan is set to get increasingly longer and longer. And it's more than just extending life - it's about extending healthy life. If we assume that the aging process can be dramatically slowed down, or even halted, it's more than likely that the older generations will continue to serve as vibrant and active members of our society. And given that seniors tend to hold positions of power and influence in our society, it's conceivable that they'll refuse to be forced into retirement on the grounds that such an imposition would violate their human rights (and they'd be correct in that assessment).

In turn, seniors will continue to lead their corporations as CEOs and CFOs. They'll hold onto their wealth and political seats, kept in power by highly sympathetic and demographically significant elderly populations. And they'll occupy positions of influence at universities and other institutions.

So I asked James Hughes how society could be hurt if an undying generation refuses to relinquish their hold on power and capital. "Again, the question should be, how is society hurt when small unaccountable elites control the vast majority of wealth?," he responded. The age of super-wealthy is pretty immaterial, he says, especially when most of the people in their age bracket will be as poor and powerless as younger cohorts.

Hughes also doesn't buy into the argument that radical life extension will result in the stagnation of society. If anything, he thinks these claims, such as risk-aversion and inflexibility, smack of ageism and simple-minded futurism. "Seniors' brains continue to make stem cells," says Hughes, "and when we are able to boost neural stem cell generation in order to forestall the neurodegeneration of aging, older people will become as cognitively flexible as younger people."

As noted in my comments above, the historical record shows that people at the top are not all that good at staying at the top for extended periods of time. There are always outliers, but they are rare in comparison to the vast majority of leaders and the famous who are just part of the churn, coming and going, displaced and quickly forgotten once their few years are done. The top of a pyramid is a challenging place to stand.

This paper examines some aspects of aging in the liver, giving a general review in the course of getting to a discussion on immune system changes that occur in aging and their influence on the liver. Note the importance of a buildup of unwanted protein byproducts inside liver cells, something that occurs due to the progressive failure of cellular housekeeping components known as lysosomes. You might recall that researchers reversed aspects of liver aging in mice a few years back by boosting lysosomal activity, so as to counteract some of the usual decline.

Although the human liver is not unscathed by the process of aging, the changes it undergoes are minor compared with other organ systems. It has been ascertained that there are no liver diseases specific to advanced age. However, the clinical course and management of liver diseases in the elderly may differ in several aspects from those of younger adults.

Human and experimental studies suggest that, in comparison with other organs, the liver ages fairly well. Aging is however associated with a variety of morphological changes in the liver, but their underlying mechanisms are still unclear. The liver progressively shrinks by 20-40% during the course of a human life, and there is a concomitant age-related decrease in liver volume. The classic gross appearance of the liver in the elderly is known as "brown atrophy", and the brown is due to an accumulation of highly oxidized insoluble proteins, known as lipofuscin, stored into hepatocytes. These accumulations of highly cross-linked protein are thought to relate to chronic oxidative stress and a failure to degrade damaged and denatured proteins. Increasing evidence suggests that lipofuscin interferes with complex cellular pathways.

One of the most important age-related changes in liver function observed in animal models is a significant decrease in regenerative capacity of the liver, but not in the capacity to restore the organ to its original volume. [It] has also been shown that aging is associated with multiple changes in. Elderly humans secrete less bile acid, have increased biliary cholesterol levels, and show an increased oxidative stress that is mainly attributable to a reduced capacity to eliminate metabolically generated superoxide radicals as efficiently as before. The reduction in hepatic blood flow during aging reduces the metabolism of rapidly cleared drugs. Aging of the liver is also associated with impaired metabolism of drugs, adverse drug interactions, and susceptibility to toxins.

Link: http://dx.doi.org/10.1186/1742-4933-10-9

Commentary on various recently published research relevant to the SENS view of biotechnology to repair and reverse aging appears as an occasional feature at the journal Rejuvenation Research. The latest is open access, so take a look at the PDF format paper, containing commentaries such as this one on a method of wrapping enzymes in polymer nanocapsules to ensure their delivery to specific locations within cells or the body:

The accumulation of recalcitrant waste substances in cells' lysosomes is implicated in a wide spectrum of aging-related diseases, including atherosclerosis, age-related macular degeneration (AMD), and many others. Being one of the clearest examples of the build-up of "junk" in aging bodies, it is expected that means to degrade lysosomal waste will be among the first rejuvenation biotechnologies to reach clinical application.

Indeed, the required development time before an effective therapy can be deployed is expected to be so brief that SENS Research Foundation devotes a substantial portion of its budget to identifying and refining enzymes for just this purpose. However, this tight schedule poses a specific problem; it is quite probable that hydrolases effective, for example, against 7-ketocholesterol (the dominant "junk" molecule in atherosclerotic plaque) or A2E18 (predominant in AMD) will be ready for clinical use before safe and effective somatic gene therapy becomes available.

It will therefore be necessary to introduce these garbage-clearing enzymes into patients directly, rather than by genetically engineering the recipient's cells to produce them - an approach termed enzyme replacement therapy, currently in widespread clinical use to treat congenital lysosomal disorders. Of course, enzymes introduced into the body by such methods cannot be replaced once degraded (a particularly rapid fate in the harsh conditions of the lysosome), necessitating regular infusions to maintain their function. The polymer-coating method described in this study enhances the hardiness of the enzymes thus treated, and might be reasonably expected to thus appreciably reduce the required frequency of reintroduction, and/or minimise the dosages required (and hence any side-effects).

Link: http://online.liebertpub.com/doi/pdf/10.1089/rej.2013.1426

What is aging? This deceptively simple question will garner you lengthy answers from the scientific community - many different lengthy answers, as it happens, some of which are even long enough to take the form of entire, complete books. There is a lot to be said on aging, and vast repositories of data, and yet there remain numerous different camps with different detailed definitions of aging - it's cause, its progression, and how best to build therapies that might slow or reverse aging.

So you have the definition put forward by Michael Rose and colleagues, or the hyperfunction theories that seem to be gaining ground among researchers of the small programmed aging camp, or the collection of mainstream views - many different interpretations and variants - that paint aging as a matter of accumulated damage.

And that is just on the matter of causes and mechanisms. The territory becomes much more of a jungle once you start down the path of asking whether aging is a disease, or whether it is a bad thing, or whether should be treated and ameliorated through medical science. Believe it or not there remain numerous researchers in the field who believe that aging should be studied but not treated, slowed, or reversed, despite the suffering and death it causes. Here is an open access opinion piece on this topic from Aubrey de Grey, via the Rejuvenation Research journal.

The desperate need for a biomedically useful definition of "aging" (PDF)

Surely everyone who studies the biology of aging fundamentally agrees on what it is they are studying, even if they may prefer somewhat different terminology to define it? I'm afraid you'd be wrong. Disagreement within the field about what aging really is and is not is very far from purely semantic, and the substance of those disagreements leads to profound differences of opinions concerning both what research gerontologists should prioritise and how they should communicate their work to others.

First: is aging a disease? Some gerontologists will just tell you "No, it is separate from age-related diseases". Some will say "No, but it is a risk factor for age-related diseases". Some will say "No, it is the set of precursors of the age-related diseases". Some will say "Yes, it is the set of precursors of the age-related diseases"! Self-evidently, whether X is a Y depends not only on the definition of X but also on the definition of Y, so one might excuse this chaos on the basis of a failure to agree on what is and is not a disease - and there is indeed no such agreement. But it gets worse.

Is aging a thing that is amenable, in principle, to medical intervention? Not if you believe the protestations of such eminent gerontologists as Bruce Carnes and Jay Olshansky, who in a recent paper critiquing (I employ classic British understatement in my choice of words here) various colleagues' work made, in spite of reviewers' efforts to educate them, the assertion that "What Wilmoth fails to acknowledge is that in order to reduce death rates at advanced ages to zero or close to it, our biology would need to be modified" (my emphasis). This sort of language, without stating explicitly that medicine can never maintain the body in a state of health so youthful that death rates will be vastly lower than today, unequivocally seeks to convey that view. So, do other gerontologists agree? Indeed they do not: if any evidence were needed, I may merely cite the fact that almost every mainstream conference on the biology of aging these days has a subtitle referring to delaying or even reversing aging.

Finally, is aging even a bad thing? At least here we find broad consensus among biogerontologists - those who study the biology of aging (though there are a few exceptions). But the same does not apply to all gerontologists: those whose field is more on the clinical, or the sociological, side tend to be among the most viciously and vocally opposed to any talk (let alone action) concerning actually doing anything about aging. As an example, a very senior (and, I am afraid to say, highly influential) clinical gerontologist from Canada recently wrote to me as follows: "I do not wish in any way shape or form to have my name associated with anti-aging medicine, regenerative or restorative medicine or some such". No kidding. I will be interested to discover, at some point, whether she is willing to defend that view publicly.

It should by now be apparent that there is a bit of a problem. Let me emphasise, however, just how much of a problem. At present, translational biogerontology (alternatively, biomedical gerontology) commands an absolutely minuscule proportion of the medical research budget of any industrialised nation. Why? Simply because the idea that postponing aging is a feasible and valuable goal, both socially and economically, has failed - despite the best efforts of many biogerontologists over many decades - to gain any significant traction among funding bodies.

I contend that gerontologists' muddled thinking outlined above concerning what aging really is is actually the number one reason for this failure.

An open access review on the topic of aging and longevity, largely focused on mainstream work aimed at producing ways to gently slow aging by metabolic manipulation:

Aging drives disease. Nearly every major killer in developed countries shares a common feature: your risk of getting the disease increases dramatically as you get older. For example, the likelihood of being diagnosed with Alzheimer's disease doubles every five years after the age of 65. A similar kind of relationship can be seen for most types of cancer, heart disease, diabetes, kidney disease, and many others. What is it about getting older that simultaneously increases risk for all of these disorders? Are there common molecular changes that cause an organism to switch from youthful and healthy to aged and infirm? Can we intervene in this process to do something about it? These are some of the big questions that scientists who study the biology of aging are interested in answering.

The perspective that most age-related disorders share a common underlying biology is a departure from traditional biomedical science, one that potentially offers a more powerful approach towards improving human health. Rather than focus on curing the individual disease, interventions that target the molecular processes of aging can simultaneously delay the onset and progression of most age-related disorders. Such an intervention is predicted to have a much larger effect on life expectancy than can be attained by treating individual diseases. This is because even if one disease is cured, the relationship between age and all the other disorders of aging still holds. For example, it has been estimated that curing cancer will lead to only a 3-5 year increase in survival for an average 50 year-old woman, while slowing aging to an extent that is routine in laboratory organisms has about a 5-10-fold greater impact on life expectancy.

Importantly, these added years from slowing aging are spent largely free from chronic disease and disability, while the relatively small gains in survival by curing cancer (or any other individual disease of aging) are still associated with the inevitable age-related declines in function of every other bodily system. This concept of extending the period of life spent free from chronic disability and disease, referred to as healthspan, is a critically important idea in the field of aging-related research.

Link: http://dx.doi.org/10.12703/P5-5

Following on from research noted last year:

Genetically engineered immune cells can drive an aggressive type of leukaemia into retreat, a small clinical trial suggests. The results of the trial - done in five patients with acute lymphoblastic leukaemia - [represent] the latest success for a 'fringe' therapy in which a type of immune cell called T cells are extracted from a patient, genetically modified, and then reinfused back. In this case, the T cells were engineered to express a receptor for a protein on other immune cells, known as B cells, found in both healthy and cancerous tissue.

"All of our patients very rapidly cleared the tumour. The treatment worked much faster than we thought." The next step [is] to move the technique out of the 'boutique' academic cancer centres that developed it and into multicentre clinical trials. "What needs to be done is to convince oncologists and cancer biologists that this new kind of immunotherapy can work."

[A researcher] remembers the day that he had to tell one of the patients in the trial that the weeks of high-dose chemotherapy the 58-year-old man had endured had not worked after all. "It was painful to have that conversation. He tells me now it was the worst news he has ever heard in his life." Another month in the hospital on intensive chemotherapy drugs did nothing to help. By the time the man started the trial, 70% of his bone marrow was tumour.

[Researchers] then extracted T cells from the patient and engineered them to express a 'chimeric antigen receptor', or CAR, that would target cells expressing a protein called CD19. Because CD19 is found on both healthy and cancerous B cells, the engineered T cells were unable to discriminate between the two. However, patients can live without B cells.

By two weeks after the procedure, the patient was showing signs of improvement. The treatment had driven his cancer into remission - as it did for the other four patients in the trial - so he became eligible for a bone-marrow transplant. A hundred days later, he is doing well. Four of the five patients were well enough to receive transplants; the remaining patient relapsed and was ineligible.

Link: http://www.nature.com/news/engineered-immune-cells-battle-acute-leukaemia-1.12643

In some circles within the aging research community it is taken as read that accumulating damage to nuclear DNA - the DNA that resides in the nucleus of your cells - contributes to degenerative aging, most likely by causing cellular maintenance and other programs to run awry to an ever increasing degree. The nucleus of the cell is well protected, and equipped with extremely efficient DNA repair mechanisms, but nonetheless damage accumulates across the years. Being alive necessarily involves the generation of reactive chemical compounds, and sooner or later some of them run into the structure of DNA within a cell and react with it. The processes of DNA repair, while ever watchful, slip up once in a while and fail to fix the resulting breakage. Every cell bears its load of unrepaired mutations.

This sort of ongoing stochastic damage is certainly a contributing cause of cancer: the more mutations you suffer, the greater the chance that one or more of them manage to alter cellular programming in just the right way to create a cancerous cell, readily to act as the seed of a malignant neoplasm. That's just a numbers game - you can be unlucky and suffer cancer young, but you are far more likely to suffer cancer later in life.

But is nuclear DNA damage a cause of general degenerative aging? Is it actually a contributing cause of frailty, failing tissue maintenance, failing organs, and so forth? The point can be argued; Aubrey de Grey puts forward the position that the levels of nuclear DNA damage experienced don't rise to producing any significant effect outside of cancer risk over a human lifetime. If we live far longer than our ancestors, as we hope we might, this damage will probably become something that has to be dealt with at some point - perhaps via swarms of adaptive medical nanorobots akin to the chromallocytes envisaged by Robert Freitas.

Standing on the side of those who argue for DNA damage as a cause of aging is the data resulting from the study of various DNA repair deficiency conditions, many of which present what appear to be the symptoms of accelerated aging, in addition to raised cancer risk. There is also the connection between DNA damage and increased cellular senescence - an accumulation of senescent cells is also thought to cause some portion of degenerative aging, and recent work has shown benefits in mice by their removal.

Via Extreme Longevity, my attention was drawn to a recent paper that adds more weight to the idea that nuclear DNA damage isn't in and of itself as important to aging as might be thought:

DNA damage in normally and prematurely aged mice

Steady-state levels of spontaneous DNA damage, the by-product of normal metabolism and environmental exposure, are controlled by DNA repair pathways. Incomplete repair or an age-related increase in damage production and/or decline in repair could lead to an accumulation of DNA damage, increasing mutation rate, affecting transcription and/or activating programmed cell death or senescence. These consequences of DNA damage metabolism are highly conserved and the accumulation of lesions in the DNA of the genome could, therefore, provide a universal cause of aging.

An important corollary of this hypothesis is that defects in DNA repair cause both premature aging and accelerated DNA damage accumulation. While the former has been well-documented, the reliable quantification of the various lesions thought to accumulate in DNA during aging has been a challenge.

Here, we quantified inhibition of long distance PCR as a measure of DNA damage in liver and brain of both normal and prematurely aging, DNA repair defective mice. The results indicate a marginal, but statistically significant, increase of spontaneous DNA damage with age in normal mouse liver but not in brain. Increased levels of DNA damage were not observed in the DNA repair defective mice. We also show that oxidative lesions do not increase with age.

These results indicate that neither normal nor premature aging is accompanied by a dramatic increase in DNA damage. This suggests that factors other than DNA damage per se, e.g., cellular responses to DNA damage, are responsible for the aging phenotype in mice.

Nuclear DNA isn't your only DNA. The mitochondria swarming in your cells carry their own lesser portion of DNA - this is far more vulnerable to harm, and damage has far greater consequences given the central importance of mitochondria in metabolism. Progressive damage to mitochondrial DNA most likely provides one of the greatest contributions to degenerative aging, given that mitochondrial function and resistance to damage appear to be one of the most important determinants of differences in life span between species.

One lesser branch of regenerative medicine is involved in searching the animal kingdom for examples of potent regeneration and seeking to understand the mechanisms involved. For example, there is the quest to discover whether the potential for salamander-like organ and limb regeneration, observed in many lower species, lies dormant in mammals by virtue of being an ancient process, evolved long ago and shared across most species. The jury is still out on that question - more work is needed.

Searching for exceptional regeneration in mammals is also a viable strategy - there are fewer instances, but the thinking is that whatever mechanisms are involved would be easier to introduce to humans. Deer antlers are one of the better known examples, and here researchers dig into some the cellular biochemistry involved. This is a small start; there are actually very few researchers looking at deer in this way, probably fewer than are, say, working with regeneration in salamanders or zebrafish:

A team of researchers [have] reported finding evidence that deer antlers - unique in that they regenerate annually - contain multipotent stem cells that could be useful for tissue regeneration in veterinary medicine. "We successfully isolated and characterized antler tissue-derived multipotent stem cells and confirmed that the isolated cells are self-renewing and can differentiate into multiple lineages. Using optimized culture conditions, deer antler displayed vigorous cell proliferation."

Deer antler is of interest, said the researchers, "because antlers are very peculiar organs in that they are lost and re-grown annually....a rare example of a completely regenerating organ in mammals." According to the researchers, they subjected deer antler to differentiation assays for osteogenic (bone), adipogenic (fat) and chondrogenic (cartilage) lineages under culture conditions specific for each lineage to confirm the multi-lineage differentiation ability of antler multipotent stem cells. They concluded that deer antler tissue might be a "valuable source of stem cells" that could "be a potentially useful source of regenerative therapeutics in veterinary science."

The researchers noted that the development of deer-specific antibodies "is essential to confirm the identification of antler multipotent stem cells". They specifically noted that injury to wild animals, including deer, might be treated using deer antler derived cells. They also pointed out that studies involving the use of horse stem cells have found clinical application of equine-derived stem cells.

Link: http://www.eurekalert.org/pub_releases/2013-03/ctco-cts031913.php

This has the look of something that might lead to an intermediary therapy for Alzheimer's disease, one that allows patients to better function despite beta amyloid build up - but it will be compensatory only, and won't solve the underlying damage and dysfunction of aging that causes beta amyloid to accumulate in the first place.

The scientific community so far has widely accepted that Alzheimer's disease is caused by the accumulation of a peptide called Amyloid beta. When Amyloid beta is applied to neurons, neuronal morphology becomes abnormal and synaptic function is impaired. However, how Amyloid beta causes dysfunction is unknown. [New] research indicates that the presence of Amyloid beta triggers increased levels of a signaling protein, called centaurin alpha 1 (CentA1), that appears to cause neuronal dysfunction - a potentially groundbreaking discovery that uncovers an important intermediary step in the progression of the disease.

As part of the research, the scientists were able to identify CentA1 and measure its negative effects on neurons. Utilizing an RNA silencing technique, they turned down the cellular production of CentA1, and showed that affected neurons, exposed to Amyloid beta and exhibiting Alzheimer's related symptoms, returned to normal morphology and synaptic function, even with the continued presence of Amyloid beta. They further found that increased CentA1 activates a series of proteins, and these proteins form a signaling pathway from CentA1 to neuronal dysfunction. Thus, inhibiting other proteins in the pathway also "cured" affected neurons.

The initial tests reported were conducted on rat brain slices. [Researchers have] already started to expand their studies to mouse models of Alzheimer's disease and preliminary experiments show promising results.

Link: http://www.eurekalert.org/pub_releases/2013-03/rci-mpf031913.php

Nick Bostrom's Fable of the Dragon-Tyrant is a noted modern morality tale, written to highlight our acceptance of death by aging, and more importantly our grand, widespread failure to work towards building therapies to treat aging. Even though the research community now knows enough to achieve that goal, and even though biotechnology is in the midst of an unprecedented revolution in capacity and capabilities, research aimed at producing human rejuvenation is hardly funded at all in comparison to other more prosaic fields.

Further, if asked, most people gladly declare that they have no interest in living longer or treating aging as a disease to be cured - despite the fact that they would no doubt be among the masses taking advantage of rejuvenation therapies were those treatments available, just as they now take advantage of modern medicine unavailable to their ancestors. So we march towards death and suffering, doing next to nothing about this avoidable fate. It is this sort of everyday madness that inspires the writing of fables.

You might recall that a couple of years back there was some talk of animating the Fable of the Dragon-Tyrant. This was generally agreed to be a good idea. I'm pleased to note that someone actually went ahead and did it:

Nick Bostrom's philosophical parable about death recounts the tale of the most vicious dragon that ate thousands of people everyday, and of the actions of the king, the people and an assembly of Dragonologists to destroy this ancient threat. Our situation with regards to human senescence is similar to the situation of the people in the fable in regard to the dragon. Therefore, we have compelling reasons to get rid of human senescence.

If you appreciated the Fable of the Dragon-Tyrant, you might also look at Bostrom's Letter from Utopia.

Your body is a deathtrap. This vital machine and mortal vehicle, unless it jams first or crashes, is sure to rust anon. You are lucky to get seven decades of mobility; eight if you be fortune's darling. That is not sufficient to get started in a serious way, much less to complete the journey. Maturity of the soul takes longer. Why, even a tree-life takes longer. Death is not one but a multitude of assassins. Do you not see them? They are coming at you from every angle. Take aim at the causes of early death - infection, violence, malnutrition, heart attack, cancer. Turn your biggest gun on aging, and fire. You must seize the biochemical processes in your body in order to vanquish, by and by, illness and senescence.

Some press for the 2045 Initiative:

Russian multi-millionaire is targeting the business community to raise money to fund a project that aims to make immortality a reality by 2045. It may sound like something straight out of a science fiction novel, but Dmitry Itskov, a 35-year-old media mogul, is seeking investors to fund research for technology that will make eternal life possible by transferring human consciousness in an artificial form to avatars (robotic bodies).

Itskov is the founder of Initiative 2045, a non-profit organization focused on creating an international research center where scientists will research and develop the technologies to make eternal life possible. Last year, Itskov wrote a public letter to individuals on Forbes billionaires list asking them to invest in his project. While Itskov did not receive any public responses, he did accomplish his goal of getting word out about the project and he is continually in talks with wealthy individuals about his project, he said.

"The goal was to get the public's attention," Itskov said. "I do communicate with some of the richest people in the world, but I can't share who they are." This summer, Itskov will make a pitch to not only to the world's most wealthy individuals, but the entire business community, to invest in his project as well as research and development in areas that help further his cause. In June, Itskov's organization will be hosting the second annual Global Future 2045 World Congress, an event where leading scientists, technologists and entrepreneurs will gather to discuss and demonstrate new technologies that are paving the way for life expansion.

Link: http://finance.yahoo.com/news/russian-tycoon-bets-immortality-125538299.html

An interview on the topic of cryonics, the low-temperature preservation of the body and brain following death. This aims to preserve the brain's fine structure - where the data of the mind is stored - so as to enable a chance at the development of future technologies to restore that individual to life:

Cryonics is based on a bet about the future, that technology will advance. A bet that we think is very sound, but is it evidence-based, it's not. Some people say, well do you have faith in cryonics? No, I just look at history and think this is a good bet. It's not certain by any means, but it's the best alternative. And that's how [Robert Ettinger] approached things. I mean, he wrote some articles about probability theory and what he called the probability of rescue. So cryonics was always from the first, scientifically based, and though there were people at the time who said this isn't going to happen, my father always challenged them and said, what's your evidence?

Is the damage [caused by freezing] so limited that you can freeze and revive a person today? It is not. I mean, there is too much damage that we cannot reverse currently for that, but that's part of why you need more time, but people frozen have the time. [Robert Ettinger] said that what some people want, will not be satisfied. Some people will not be satisfied until someone is frozen, and revived, and lives forever. Well, we can't wait for them.

The quicker you do it, the less damage will occur. And the process begins with cooling of the body, and especially the head, sometimes while continuing to pump the blood so that oxygenated blood flows to the brain and that limits the damage in the meantime. The next step is, and the cooling goes through several steps, starting with ice, then the body is perfused with cryoprotective agents to protect against damage in the freezing. You know, the next stage is dry ice and then liquid nitrogen vapors and ultimately liquid nitrogen, and the entire process takes a couple of days, takes a few days, really, to be finished.

Link: http://www.huffingtonpost.com/2013/03/18/cryonics-death-video_n_2883492.html

Sonia Arrison is the author of 100 Plus, published back in 2011:

To my eyes, the book is essentially a fast overview of the last ten years of science, debate, important subjects, and noteworthy people in the aging research and longevity advocacy communities. A survey of the historical and mythological roots of present day attitudes serves as a springboard into a fast look at some of the important lines of medical research and development - SENS, tissue engineering, longevity genes, and so forth. Then it's off to observe the squawking of Malthusians and their resource-based objections to engineering greater human longevity, followed by a side-trip into philosophical discussions of longevity, and then a soujourn in the realm of economics to talk seriously about how the length of life shapes society.

100 Plus is, I think, a good book to give to the average fellow in the street who would be flattened and slain by the attempt to read Aubrey de Grey and Michael Rae's Ending Aging. That book is where the meat is - but 100 Plus is a Cliff's Notes for the current state and direction of longevity science and the advocacy community supporting it. That is a useful thing: a person reading 100 Plus will wind up in roughly the same place as a casual reader of the high points of Fight Aging!.

Video of Arrison presenting on this general set of topics at TEDx earlier this year has made its way to YouTube for those of us not in the neighborhood. Take a look:

Left to its own devices, your immune system supports a fairly fixed upper limit of T-cells, and the fraction of those cells that can respond effectively to new threats, or patrol the body to destroy senescent or precancerous cells, declines with age. On the one side ever more T-cells become specialized in futile attempts to deal with persistent but otherwise not terribly threatening viruses such as CMV, and thus become useless for other activities. On the other side, the new supply of T-cells dwindles to nothing as the thymus atrophies - a process called thymic involution, something that happens comparatively early in life.

So a range of possible approaches could be taken to restore a sufficient number of aggressive T-cells to the body. Using stem cell technologies to create large numbers of a patient's own T-cells and then infuse them periodically, for example - that's possible today, but only being tried in trials for specific named diseases, as is usually the case for things that might be beneficial to all old people. Hopefully overseas clinics and medical tourism will pick up the slack. Other approaches involve destroying the unneeded specialized cells to free up immune system capacity, or trying to increase the supply of new immune cells by at least partially regenerating and restoring the thymus.

The thymus is a thumb-sized organ just above the sternum where our immune cells are trained to recognize self from other. It is fully developed by the time we are 10 years old, but after that it begins gradually to shrink. By age 25, it has already lost 30% of its mass, and by age 60 it is less than half its peak size. There is evidence that this is related to the immune decline that contributes so much to growing mortality risk with age, and that reversing that decline might lead to longer, healthier lives.

Research on reversal of thymic [degeneration] is a backwater of medical science. If this is an opportunity for major gains in life expectancy, then it is a neglected opportunity that has attracted little interest or funding. Based on evolutionary arguments, the general attitude seems to be that if the thymus shrinks over a lifetime, then it must not be much needed; or, conversely, that a Law of Nature assures us that any therapy to maintain its function must necessarily have dangerous side-effects that outweigh the benefits. [But] this is ideology, a misplaced faith in general theory over explicit experimental results. Reality in the lab appears to be that: "Thymic involution [seems] to provide no obvious benefits in humans that would outweigh the benefits of [its] elimination once the hazards associated with such issues as insulin-like signaling can be set aside."

Link: http://joshmitteldorf.scienceblog.com/2013/03/03/halting-thymic-involution/

Microglia are immune cells of the central nervous system (CNS). As is the case for the rest of the immune system, they are involved in the rising levels of chronic inflammation that accompany aging, inflammation that contributes to the development of neurodegenerative disease. Here is an open access review on this topic and the prospects for intervention:

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and age-related macular degeneration (AMD), share two characteristics in common: (1) a disease prevalence that increases markedly with advancing age, and (2) neuroinflammatory changes in which microglia, the primary resident immune cell of the CNS, feature prominently. These characteristics have led to the hypothesis that pathogenic mechanisms underlying age-related neurodegenerative disease involve aging changes in microglia. If correct, targeting features of microglial senescence may constitute a feasible therapeutic strategy.

This review explores this hypothesis and its implications by considering the current knowledge on how microglia undergo change during aging and how the emergence of these aging phenotypes relate to significant alterations in microglial function. Evidence and theories on cellular mechanisms implicated in driving senescence in microglia are reviewed, as are "rejuvenative" measures and strategies that aim to reverse or ameliorate the aging microglial phenotype. Understanding and controlling microglial aging may represent an opportunity for elucidating disease mechanisms and for formulating novel therapies.

Link: http://www.frontiersin.org/Cellular_Neuroscience/10.3389/fncel.2013.00022/full

Advances in medical biotechnology happen constantly, and every field that is working towards long-term goals - such as, say, growing new organs from scratch or gaining sufficiently control over cells to repair and rejuvenate organs in situ - spins off new and incrementally better applications at each waypoint on the road. Every narrow field of applied life sciences has it's aura of new technologies and partial implementations.

So for the liver: one end goal would be the ability to simply grow livers on demand from a patient's own cells, another to reliabily trigger liver regrowth to the same degree as happens in lower animals. Still another is to repair damage and dysfunction globally in the liver's cells, so as to restore it to youthful capacity and function. The foundations for all of these goals are under construction, and along the way we see all sorts of interesting practical applications of biotechnology.

Here are a few such appications from recent news releases, with an emphasis on integration of biology with machinery, something that we'll be seeing a lot more of in the years ahead. These are first steps along a road that will see part-machine-part-biological tissues competing with artificially grown but otherwise wholly biological tissues, until such time as that distinction begins to blur at the edges with the advent of advanced forms of molecular nanotechnology.

Machine that preserves liver outside body offers new hope to transplant patients

At present, donated livers are cooled to 4C (39.2F) to preserve them, but this process does not stop them from deteriorating and they can only be stored for about 12 hours. The machine developed by scientists at Oxford University warms the organ to body temperature and circulates a combination of blood, oxygen and nutrients through it, allowing it to function just as it would inside a human body.

Researchers are confident they will be able to keep donor organs alive for 24 hours, and pre-clinical tests suggest it may be possible to preserve them for 72 hours or more. Modified versions of the portable device, which is the size of a supermarket shopping trolley, could also help transplants of other organs, including the pancreas, kidneys and lungs, and could be used to test the toxicity of new medicines.

Artificial human livers engineered for drug testing and discovery

Researchers have now made it possible for companies to predict the toxicity of new drugs earlier, potentially speeding up the drug development process and reducing the cost of manufacturing. The tool they have engineered to enable this is an artificial human liver piece, which mimics the natural tissue environment closely.

[These] liver tissue models for drug toxicity testing [consist of a ] three-dimensional porous scaffold that enables liver cells to spontaneously assemble into three-dimensional liver spheroids. These spheroids strongly resemble liver tissue. [By] seeding liver cells within a microfluidic system, the micro device is used to screen the liver's capacity to process different drugs and other compounds.

Using [a] microfabricated microporous membrane, the liver cells are sandwiched between the membranes, which can control the transfer of drugs, nutrients and oxygen to the cells, and provide more reliable and reproducible screening results. The membrane surface has been engineered to simulate liver cell interaction with [the extracellular matrix] and promote formation of liver tissues after the cells are seeded. Experiments have shown that the microporous membranes can maintain long-term liver cell functions for more than two weeks and will be useful for chronic liver toxicity testing, and industry-scale drug screening.

Team first to grow liver stem cells in culture, demonstrate therapeutic benefit

In a previous [study], investigators [were] the first to identify stem cells in the small intestine and colon by observing the expression of the adult stem cell marker Lgr5 and growth in response to a growth factor called Wnt. They also hypothesized that the unique expression pattern of Lgr5 could mark stem cells in other adult tissues, including the liver, an organ for which stem cell identification remained elusive.

[Researchers] used a modified version of [this method] and discovered that Wnt-induced Lgr5 expression not only marks stem cell production in the liver, but it also defines a class of stem cells that become active when the liver is damaged. The scientists were able to grow these liver stem cells exponentially in a dish - an accomplishment never before achieved - and then transplant them in a specially designed mouse model of liver disease, where they continued to grow and show a modest therapeutic effect. "We were able to massively expand the liver cells and subsequently convert them to hepatocytes at a modest percentage. Going forward, we will enlist other growth factors and conditions to improve that percentage. Liver stem cell therapy for chronic liver disease in humans is coming."

Here is a piece to act as fuel for people who like to argue policy and don't look much beyond the now. I think this is chiefly interesting for the potential support it gives to lifestyle differences between the genders as a noteworthy contributing cause to the fact that women live longer. Otherwise, it reinforces the point that differences in life expectancy at birth between regions or over time is not all that relevant to the intersection of medicine and aging - more attention should be given to statistics for life expectancy at 50 or 60.

Higher mortality rates among Americans younger than 50 are responsible for much of why life expectancy is lower in the United States than most of the world's most developed nations. The research [found] that excess mortality among Americans younger than 50 accounted for two-thirds of the gap in life expectancy at birth between American males and their counterparts and two-fifths between females and their counterparts in the comparison countries.

Most of the excess mortality of those younger than 50 was caused by noncommunicable diseases, including perinatal conditions, such as pregnancy complications and birth trauma, and homicide and unintentional injuries including drug overdose, a fact that she said constitutes a striking finding of the study. "These deaths have flown under the radar until recently. This study shows that they are an important factor in our life expectancy shortfall relative to other countries."

You get further in life by comparing what you have to what is possible, not with what other people have. But relativism of status, circumstances, and possessions is deeply set into the human mind. It's ever a struggle to get people to look beyond what is to see what might be.

Link: http://www.upenn.edu/pennnews/news/penn-study-links-us-mortality-rates-under-age-50-us-life-expectancy-lagging-other-high-income-c

An example of an application of induced pluripotent stem cells moving closer to use in humans. The transplant of new brain cells is a potential treatment for a range of neurodegenerative conditions:

Scientists have transplanted neural cells derived from a monkey's skin into its brain and watched the cells develop into several types of mature brain cells. [After] six months, the cells looked entirely normal, and were only detectable because they initially were tagged with a fluorescent protein. Because the cells were derived from adult cells in each monkey's skin, the experiment is a proof-of-principle for the concept of personalized medicine, where treatments are designed for each individual.

And since the skin cells were not "foreign" tissue, there were no signs of immune rejection - potentially a major problem with cell transplants. "When you look at the brain, you cannot tell that it is a graft. Structurally the host brain looks like a normal brain; the graft can only be seen under the fluorescent microscope."

The transplanted cells came from induced pluripotent stem cells (iPS cells), which can, like embryonic stem cells, develop into virtually any cell in the body. iPS cells, however, derive from adult cells rather than embryos. In the lab, the iPS cells were converted into neural progenitor cells. These intermediate-stage cells can further specialize into the neurons that carry nerve signals, and the glial cells that perform many support and nutritional functions. This final stage of maturation occurred inside the monkey.

Link: http://www.news.wisc.edu/21595

A great many researchers are presently engaged in amassing data on human longevity. There are the longitudinal studies running for decades, familial studies searching for measures of inheritance in long-term health, the vast statistical epidemiological studies, and behind them all the growing databases of various biological measurements, taken in ever greater detail as the costs of doing so fall rapidly. This is all very interesting, and will ultimately lead to a complete (and very, very complex) vision of how human metabolism runs and alters throughout aging, from the uppermost and more familiar processes all the way down to cellular mechanisms and accrued damage.

But strangely, very little of this is strictly necessary in order to engineer far longer lives. We don't need to know much more than we do already about human biology in order to have a good shot at building functional rejuvenation biotechnologies. The differences between old tissues and young tissues are pretty well enumerated at this time: the remaining lack of knowledge relates to the (many, many) details of the intricate dance of molecular and epigenetic mechanisms involved in moving from young to old. That dance is what the majority of the aging research community - and the majority of funding - is involved in deciphering. But anyone with a bunch of money could short-cut all of that and stomp right down the path to rejuvenation therapies today, if they cared to do it. All that needs to happen is that the known differences between old tissue and young tissue be repaired - it doesn't matter how it happens, so long as you can repair it.

Think of it this way: a man could spend a very long time building the mathematical models needed to show exactly how paint cracks and flakes on a wall. In doing that he might learn a lot about how to create paint that lasts a little longer, or which materials make for longer-lasting painted surfaces. That's a life's labor right there. Or he could just take a day every now and then to sand off the wall and paint it over. This is essentially the same comparison between the relative amounts of labor involved in aging and longevity science - with the note that in this analogy the man needs to create the paint from scratch and chase down a horse and a tree to make the brush.

So longevity science is as much a matter of persuasion as getting the work done. We need to see more funding going to repainting and less to the general theory of decay in painted surfaces. It's very clear what needs to happen, but gathering the necessary large-scale funding for work on SENS-like rejuvenation biotechnology is a work in progress.

In any case, here's an interesting pair of papers resulting from some of the ongoing studies of human aging. Interesting doesn't necessarily mean progress towards longer lives, remember, but there's no harm in looking and learning. This first one, for example, makes one think about damage-based theories of aging - with the implication that people who live longer tend to be more robust in every way at every age, precisely because they are carrying less of a burden of damage. It is also worth looking back at unrelated work that speculatively suggests that intelligence (or better cognitive function, take your pick) correlates with longevity for genetic reasons rather than sociological or economic reasons. i.e. genes for intelligence confer greater resistance to low-level damage in cells and molecular machinery.

Familial Longevity Is Marked by Better Cognitive Performance at Middle Age: The Leiden Longevity Study

Decline in cognitive performance is a highly prevalent health condition in elderly. Offspring of nonagenarian siblings with a familial history of longevity have better cognitive performance compared to the group of their partners of comparable age. This effect is independent of age-related diseases and known possible confounders. Possible explanations might be differences in subclinical vascular pathology between both groups.

And here is another in a line of papers noting that long-lived humans appear to be subtly different in their lipid metabolism. These lipid metabolism differences are among the few that have been reliably showing up in different populations.

Metabolic Signatures of Extreme Longevity in Northern Italian Centenarians Reveal a Complex Remodeling of Lipids, Amino Acids, and Gut Microbiota Metabolism

Here using a combined metabonomics approach [we] report for the first time the metabolic phenotype of longevity in a well characterized human aging cohort compromising mostly female centenarians, elderly, and young individuals. With increasing age, targeted [profiling] of blood serum displayed a marked decrease in tryptophan concentration, while an unique alteration of specific glycerophospholipids and sphingolipids are seen in the longevity phenotype. We hypothesized that the overall lipidome changes specific to longevity putatively reflect centenarians' unique capacity to adapt/respond to the accumulating oxidative and chronic inflammatory conditions characteristic of their extreme aging phenotype.

The smaller and shorter lived the animal, the easier it is to extend its life in the laboratory. This is in part because more experiments can run at lower cost, but also because it seems that many of the evolved, shared mechanisms for adjusting the pace of aging or degree of tissue maintenance in response to environmental circumstances (e.g. calorie restriction) have a larger effect in shorter-lived species.

Any given mechanism for lengthening life span can be triggered or partially triggered or gently influenced in numerous ways. A lot of present research is focused on enumerating these many methods, and then matching them up to the few known underlying mechanisms for lengthening life. So we see research publications like this one:

Although mitochondrial-derived oxygen radicals have been questioned as the main driving force for the aging process, changes in mitochondrial metabolism almost certainly play a role. Dietary restriction (DR), which extends lifespan, also delays the aging-induced electron transport chain dysfunction in rodents. DR increases the NAD/NADH ratio in many tissues, which stimulates mitochondrial tricarboxylic acid (TCA) cycle dehydrogenases that utilize NAD as a cofactor. The increased TCA cycle function likely necessitates increased anaplerosis, important for longevity.

Alteration of mitochondrial TCA cycle function influences lifespan in C. elegans. Malate, the tricarboxylic acid (TCA) cycle metabolite, increased lifespan and thermotolerance in the nematode C. elegans. The increased longevity provided by malate addition did not occur in fumarase (fum-1), glyoxylate shunt (gei-7), succinate dehydrogenase flavoprotein (sdha-2), or soluble fumarate reductase F48E8.3 RNAi knockdown worms. Therefore, to increase lifespan, malate must be first converted to fumarate, then fumarate must be reduced to succinate by soluble fumarate reductase and the mitochondrial electron transport chain complex II.

Lifespan extension induced by malate depended upon the longevity regulators DAF-16 and SIR-2.1. Malate supplementation did not extend the lifespan of long-lived eat-2 mutant worms, a model of dietary restriction. Malate and fumarate addition increased oxygen consumption, but decreased ATP levels and mitochondrial membrane potential suggesting a mild uncoupling of oxidative phosphorylation. Malate also increased NADPH, NAD, and the NAD/NADH ratio. Fumarate reduction, glyoxylate shunt activity, and mild mitochondrial uncoupling likely contribute to the lifespan extension induced by malate and fumarate by increasing the amount of oxidized NAD and FAD cofactors.

Link: http://dx.doi.org/10.1371/journal.pone.0058345

The next conference put on by the 2045 Initiative will be held in mid-June in New York. The initiative is backed by a wealthy Russian businessman and aims to move from biological bodies and minds to machine bodies and minds as rapidly as possible. This is not my favored path to greatly enhanced longevity - largely for reasons of efficiency and speed, as I've outlined in the past - but it is at least promising that the world's high net worth individuals are starting to see that they can do a great deal to change the state of human longevity. The costs of doing so have fallen to the point at which one billionaire could push the research and development community in the right direction by following the standard playbook for encouraging the foundation and growth of a research and development community.

Every movement has its quirks, and it remains to be seen where the focus on engineering of human culture and building bridges to religious communities, wrapped into the work on artificial bodies, will take the 2045 initiative. I'd certainly be more comfortable with more of a focus on technology and less on societal engineering involving religion. The latter has a lot of failure modes, amply demonstrated throughout history in many large and small groups:

The second international Global Future 2045 congress will take place on 15-16 June 2013 at the Lincoln Center in New York, and will be focused on discussion of a new evolutionary strategy for humanity aimed at overcoming the 21st century's civilization challenges. The strategy is based on carrying out two revolutions: spiritual and sci-tech. We believe this is the only way to overcome existing crises.

At the congress, a vision will be presented for the spiritual transformation of humanity, and new technologies will be demonstrated which are likely to form the basis of the sci-tech revolution. The congress will also showcase our Avatar science mega-project, aimed at accelerating the creation of technologies enabling a gradual transition from our biological bodies to an increasingly advanced artificial carrier of the human self.

The first GF2045 congress took place in Moscow in February 2012. Its main goal was a discussion of global threats and opportunities arising from the development of new technologies, and the formulation of recommendations for the realization of the optimal scenario for the future with regard to the expected usage of these technologies. In the world of international science, this was the first time at this level and in this form, that not only the key directions of innovations in the coming decades were examined, but also their ethical and philosophical aspects.

The main goals of the 2045 Initiative: the creation and realization of a new strategy for the development of humanity which meets global civilization challenges; the creation of optimale conditions promoting the spiritual enlightenment of humanity; and the realization of a new futuristic reality based on 5 principles: high spirituality, high culture, high ethics, high science and high technologies.

The main science mega-project of the 2045 Initiative aims to create technologies enabling the transfer of a individual's personality to a more advanced non-biological carrier, and extending life, including to the point of immortality. We devote particular attention to enabling the fullest possible dialogue between the world's major spiritual traditions, science and society.

Link: http://www.gf2045.com/

The study of mTOR, mechanistic target of rapamycin, in the context of aging and longevity in mammals has been gathering pace and funding in recent years. I expect that there will be a brace of well-funded biotech startups running through the standard, expensive, old-school path to building and commercializing drugs over the next ten years, much akin to what has been happening for suirtuin research - and with just about as little to show for it in the end, I'd imagine, although mTOR is a much better and more proven target for modestly slowing aging than are the sirtuins.

Drugs to slow aging by poking around with metabolism are not the future of longevity science; even if successful, they'll take decades to produce end results, and those end results will be largely useless for people already old. The only future with any future in it for us is SENS research and similar targeted approaches to repairing the damage of aging: ways to produce actual rejuvenation of the old. All the rest is just a distraction, and possibly a lethal one if it keeps on dominating the mainstream of research funding.

There are some quite prolific authors writing papers on the subject of mTOR, many of whom fall into the programmed aging camp. They theorize aging to be an evolved genetic and metabolic program of changes that are beneficial in youth but then run amok to cause damage and dysfunction in old age. This is as opposed to the presently more mainstream view of aging as being caused at root by a stochastic accumulation of cellular and molecular damage that then in turn leads to epigenetic and metabolic changes as our biology tries (and ultimately fails) to cope. Cart, horse, horse, cart: it is a measure of the sheer complexity of the data that the current research community can (more or less) support two completely opposite interpretations of what is actually taking place.

I favor the damage based theories (and hence SENS as a course of research and development). I think it's hard to reconcile programmed aging with the reliability theory view of aging, and the success of reliability theory in general, not to mention the large body of evidence that points toward damage repair strategies like SENS as the best step forward.

The programmed aging researchs see mTOR as a potential central mechanism to fit into their theories - something that can be adjusted and aging changes its pace. In particular, it fits in with the hyperfunction hypothesis on aging put forward of late by researchers of the programmed aging camp. This is a point of view that might gain ground in part because the cancer research community, a large force when it comes to funding and promotion of work within the life sciences, can make use of it:

Recent progress in genetics of aging, senescence and longevity: focusing on cancer-related genes

It is widely believed that aging results from the accumulation of molecular damage, including damage of DNA and mitochondria and accumulation of molecular garbage both inside and outside of the cell. Recently, this paradigm is being replaced by the "hyperfunction theory", which postulates that aging is caused by activation of signal transduction pathways such as TOR (Target of Rapamycin).

Overactivation of these sensory signal transduction pathways can cause cellular senescence, age-related diseases, including cancer, and shorten life span. Here we review some of the numerous very recent publications on the role of signal transduction molecules in aging and age-related diseases. As was emphasized by the author of the "hyperfunction model", many (or actually all) of them also play roles in cancer. So these "participants" in pro-aging signaling pathways are actually very well acquainted to cancer researchers. A cancer-related journal [is] the perfect place for publication of such experimental studies, reviews and perspectives, as it can bridge the gap between cancer and aging researchers.

As you might guess from reading between the lines, no small amount of politicking takes place in the trenches when it comes to putting forward one's theories, gathering supporters, claiming more support than there might actually be, and so forth. Here is another recent paper on the topic of mTOR as a therapeutic target to slow aging:

Rapalogs and mTOR inhibitors as anti-aging therapeutics

Rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR), has the strongest experimental support to date as a potential anti-aging therapeutic in mammals. Unlike many other compounds that have been claimed to influence longevity, rapamycin has been repeatedly tested in long-lived, genetically heterogeneous mice, in which it extends both mean and maximum life spans. However, the mechanism that accounts for these effects is far from clear, and a growing list of side effects make it doubtful that rapamycin would ultimately be beneficial in humans. This Review discusses the prospects for developing newer, safer anti-aging therapies based on analogs of rapamycin (termed rapalogs) or other approaches targeting mTOR signaling.

Another specific benefit of calorie restriction is enumerated in this primate study, one that suggests a generally lower level of damage to the brain is taking place in calorie restricted individuals. The lack of impact on β-amyloid is interesting, however, given that calorie restriction has been shown to slow near every other measurable aspect of aging:

While moderate calorie restriction (CR) in the absence of malnutrition has been consistently shown to have a systemic, beneficial effect against aging in several animals models, its effect on the brain microstructure in a non-human primate model remains to be studied using post-mortem histopathologic techniques. In the present study, we investigated differences in expression levels of glial fibrillary acid protein (GFAP) and β-amyloid plaque load in the hippocampus and the adjacent cortical areas of 7 Control (ad libitum)-fed and 6 CR male rhesus macaques using immunostaining methods.

CR monkeys expressed significantly lower levels (~30% on average) of GFAP than Controls in the CA region of the hippocampus and entorhinal cortex, suggesting a protective effect of CR in limiting astrogliosis. These results recapitulate the neuroprotective effects of CR seen in shorter-lived animal models.

There was a significant positive association between age and average amyloid plaque pathology in these animals, but there was no significant difference in amyloid plaque distribution between the two groups. Two of the seven Control animals (28.6%) and one of the six CR animal (16.7%) did not express any amyloid plaques, five of seven Controls (71.4%) and four of six CR animals (66.7%) expressed minimal to moderate amyloid pathology, and one of six CR animals (16.7%) expressed severe amyloid pathology. That CR affects levels of GFAP expression but not amyloid plaque load provides some insight into the means by which CR is beneficial at the microstructural level, potentially by offsetting the increased load of oxidatively damaged proteins, in this non-human primate model of aging.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23473840

Some characteristic differences in lipid metabolism are associated with greater human longevity; this is one of the few markers of an inherited predisposition to longevity that clearly shows up in multiple population studies. Here is more detail on this topic:

Middle aged offspring of nonagenarians, as compared to their spouses (controls) show a favorable lipid metabolism marked by larger LDL particle size in men and lower total triglyceride levels in women. To investigate which specific lipids associate with familial longevity, we explore the plasma lipidome by measuring 128 lipid species [in] 1526 offspring of nonagenarians (59 years ± 6.6) and 675 (59 years ± 7.4) controls from the Leiden Longevity Study.

In men, no significant differences were observed between offspring and controls. In women however, nineteen lipid species associated with familial longevity. Female offspring showed higher levels of ether phosphocholine (PC) and sphingomyelin (SM) species (3.5-8.7%) and lower levels of phosphoethanolamine PE (38:6) and long-chain triglycerides (TG) (9.4-12.4%). The association with familial longevity of two ether PC and four SM species was independent of total triglyceride levels.

In addition, the longevity-associated lipid profile was characterized by a higher ratio of monounsaturated (MUFA) over polyunsaturated (PUFA) lipid species suggesting that female offspring have a plasma lipidome less prone to oxidative stress. Ether PC and SM species were identified as novel longevity markers in females, independent of total triglycerides levels.

Several longevity-associated lipids correlated with a lower risk of hypertension and diabetes in the Leiden Longevity Study cohort. This sex-specific lipid signature marks familial longevity and may suggest a plasma lipidome with a better antioxidant capacity, lower lipid peroxidation and inflammatory precursors, and an efficient beta-oxidation function.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23451766

Staff at the British Institute of Arts and Ideas have been putting presentation and interview videos up on YouTube of late, presumably to help drum up traffic for their forthcoming festival of philosophy and music. (It is billed as the "world's largest philosophy and music festival", which seems a low bar to be aiming for, for all that it looks to be well assembled as an event and populated by noted speakers). A couple of videos of biogerontologist and longevity science advocate Aubrey de Grey can be found amongst those uploaded recently, the presentation below being one of them:

It has to be said that there are a lot of presentations by de Grey on YouTube now. Anyone looking for an explanation of the SENS approach to rejuvenation biotechnology or the work of the SENS Research Foundation in video format is spoiled for choice. It's getting to the point at which someone should assemble a video primer to guide newcomers to the best of the introductory presentations first, and then list the rest by topic and the degree to which you need to understand SENS and the underlying life sciences in order to appreciate it.

That said, with the SENS Research Foundation's latest redesign, sending people to watch the short videos on their homepage is a good first option.

Rapamycin extends life in mice via mechanisms that seem at least somewhat complementary to those of calorie restriction, but it isn't the sort of thing you'd want to take haphazardly given the other effects it has. Its primary use in medical practice is as an immunosuppressant, for example. Research teams have made inroads in splitting out the bad from the good, but there's a way to go there yet.

The evolutionarily conserved target of rapamycin (TOR) signaling controls growth, metabolism, and aging. In the first robust demonstration of pharmacologically-induced life extension in mammals, longevity was extended in mice treated with rapamycin, an inhibitor of mechanistic TOR (mTOR). However, detrimental metabolic effects of rapamycin treatment were also reported, presenting a paradox of improved survival despite metabolic impairment. How rapamycin extended lifespan in mice with such paradoxical effects was unclear.

Here we show that detrimental effects of rapamycin treatment were only observed during the early stages of treatment. These effects were reversed or diminished in mice treated for 20 weeks, with better metabolic profiles, increased oxygen consumption and ketogenesis, and markedly enhanced insulin sensitivity. Thus, prolonged rapamycin treatment lead to beneficial metabolic alterations, consistent with life extension previously observed. Our findings provide a likely explanation of the "rapamycin paradox" and support the potential causal importance of these metabolic alterations in longevity.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23473038

We humans are complex creatures, and variations in our longevity in any given generation can be shown to correlate with all sorts of societal line items: status, wealth, intelligence, education, happiness, and so forth. But what are the mechanisms that create these correlations? Here is a small piece of research to suggest that status, at least, doesn't seem to have a significant and consistent effect in and of itself - that correlation must be based on other related items, such as wealth or intelligence:

Research has long linked high socioeconomic status with better health and lower mortality. But what's remained unclear is whether this association has more to do with access to resources (education, wealth, career opportunity, etc.) or the glow of high social status relative to others. Scholars call the latter "relative deprivation."

To tease apart these factors, a team of investigators [studied] Baseball Hall of Fame inductees, Emmy Award winners, and former Presidents and Vice Presidents, comparing each to nominated losers in the same competition or election. The result: There were no consistent advantages for winners. The association between winning and longevity is sometimes positive, sometimes negative, and sometimes nonexistent, though the specifics are revealing. Overall, the results suggest that access to resources and opportunity is more important than relative status.

"The relative deprivation theory would predict that losers would consistently be at a disadvantage for health and longevity compared to winners, but this is not what we see." A more likely explanation [is] that the advantages and disadvantages of winning depend on the mix of opportunities and stresses that they bring. "Our findings provide an important correction to an overemphasis on relative deprivation as an explanation of health inequalities. Relative deprivation likely plays some role in health inequalities, but it is not as important as the life circumstances and opportunities that result from one's socioeconomic position."

Link: http://www.eurekalert.org/pub_releases/2013-03/asa-dwa031113.php

Sirtuin research is probably the most overhyped area of present day research into the mechanistic interactions between metabolism, health, and aging - certainly more so than for the calorie restriction studies that it branched from. This is the somewhat inevitable result of more than a billion dollars of capital going into research and development, as funding at that level always generates a bright public relations aura, plus the shills of the "anti-aging" marketplace latching on to something they can use to push new products to the gullible. The bottom line for research into sirtuins is this: (a) it's relevant if you want to learn more about the detailed operation of metabolism, and (b) it's near completely irrelevant if your goal is to live longer in good health.

The press has reacted in their normal clueless way to a recent piece of news from the researchers that first popularized SIRT1; it is essentially a defense of earlier work against the proposition that there were significant artifacts in the data caused by some of the experimental protocol details. There's nothing in this new release to change the overall story, however - that despite a decade and a billion dollars, there's nothing much to see here other than increased understanding of a narrow slice of metabolism. Little in the way of meaningful extension of life in normal rodents, no therapies to even slightly slow aging in humans, considerable dispute over the basic science, etc, etc. Give that much money to SENS research and it'd be a very different story.

New Study Validates Longevity Pathway: Findings Identify Universal Mechanism for Activating Anti-Aging Pathway

The team tested approximately 2,000 mutants of the SIRT1 gene, eventually identifying one mutant that completely blocked resveratrol's effect. The particular mutation resulted in the substitution of a single amino acid residue, out of the 747 that make up SIRT1. The researchers also tested hundreds of other molecules from the Sirtris library, many of which are far more powerful than resveratrol, against this mutant SIRT1. All failed to activate it.

The authors propose a model for how resveratrol works: When the molecule binds, a hinge flips, and SIRT1 becomes hyperactive.

Although these experiments occurred in a test tube, once the researchers identified the precise location of the accelerator pedal on SIRT1 - and how to break it - they could test their ideas in a cell. They replaced the normal SIRT1 gene in muscle and skin cells with the accelerator-dead mutant. Now they could test precisely whether resveratrol and the drugs in development work by tweaking SIRT1 (in which case they would not work) or one of the thousands of other proteins in a cell (in which they would work). While resveratrol and the drugs tested revved up mitochondria in normal cells (an effect caused activating by SIRT1), the mutant cells were completely immune.

This is plain old metabolic science - interesting stuff if you're in that line of work, but not the road to greatly enhanced human longevity. Calorie restriction has a far greater effect on human metabolism, and it's generally accepted by the research community that it only grants a marginal improvement to human life span, even while producing tremendous benefits to health. If it did more we'd certainly know about it; there are plenty of human communities that undertake calorie restriction to various degrees.

The only way that large enhancements to human longevity will happen in our lifetimes is through biotechnologies designed and targeted to repair specific forms of cellular and molecular damage that cause aging. Conveniently, this is a path that is considerably better known and less costly than even marginal attempts to change a very narrow set of mechanisms in the operation of metabolism. Consider that for the money and time spent so far on sirtuins - with no signs of coming to any sort of meaningful result any time soon - most or all of the SENS program to build rejuvenation therapies could be implemented in laboratory mice.

From where I stand, metabolic manipulation of the sort exemplified by sirtuin research is a gargantuan false path for medicine and the biotechnologies of human health. Its chief output is to steer resources away from where they might produce meaningful results in a short enough time frame to matter to those of us reading this now. Even if fabulously successful beyond the wildest dreams of the researchers involved, sirtuin research would do no more than recapitulate some of the effects of calorie restriction - that wouldn't help the old, as slowing aging doesn't help those already harmed by aging, it wouldn't reverse or repair the effects of aging, it wouldn't even be as effective as actual calorie restriction. In no way would any of this add decades of healthy years to life; there is simply no path to that end goal via the likes of Sirtris and similar groups working on sirtuins or other calorie restriction mimetic mechanisms.

While we're on the subject, here are two more recent research publications on the topic of sirtuins; all quite interesting, all of little value when it comes to the only metric that really matters, which is the ability to revert the course of degenerative aging.

The sirtuins, oxidative stress and aging: an emerging link

Reactive oxygen species (ROS) are a family of compounds that can oxidatively damage cellular macromolecules and may influence lifespan. Sirtuins are a conserved family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases that regulate lifespan in many model organisms including yeast and mice.

Recent work suggests that sirtuins can modulate ROS levels notably during a dietary regimen known as calorie restriction which enhances lifespan for several organisms. Although both sirtuins and ROS have been implicated in the aging process, their precise roles remain unknown. In this review, we summarize current thinking about the oxidative stress theory of aging, discuss some of the compelling data linking the sirtuins to ROS and aging, and propose a conceptual model placing the sirtuins into an ROS-driven mitochondria-mediated hormetic response.

While considerable more investigations are required, a causative role for oxidative stress in aging remains one of the most solid aging theories [and] sirtuins are intimately linked to the cellular response to oxidative stress. Moving forward, it will be important to develop experimental models in which the levels of oxidative stress and the activities of sirtuins can be precisely modulated to determine if sirtuins have a causative role in lifespan extension. Does mitochondrial sirtuin overexpression in mice extend lifespan? Do long-lived animals exhibit chronic low levels of oxidative stress? From a more practical standpoint, is it possible to rejuvenate tissue function by targeted overexpression of sirtuins to reduce oxidative stress? We look forward to future studies that will undoubtedly address many of these important questions.

Sirt1 activation by resveratrol is substrate sequence-selective

Sirtuins are protein deacetylases used as therapeutic targets. Pharmacological Sirt1 activation has been questioned since the in vitro activator resveratrol failed to stimulate deacetylation of several physiological substrates. We tested the influence of substrate sequence by analyzing resveratrol effects on Sirt1-dependent deacetylation of 6802 physiological acetylation sites using peptide microarrays.

Resveratrol stimulated deacetylation of a small set of sites and inhibited deacetylation of another set, whereas most substrates were hardly affected. Solution assays confirmed these substrate categories, and statistical analysis revealed their sequence features. Our results reveal substrate sequence dependence for Sirt1 modulation and suggest substrates contributing to resveratrol effects.

The substrate sequence-dependent effect would explain why resveratrol has Sir2-dependent effects in C. elegans overlapping with, but not identical to, the effects of Sir2 overexpression, and why resveratrol failed to stimulate Sirt1 against some substrates.

Carrying excess fat tissue for years in youth and mid-life is associated with a greater risk of age-related disease and a shorter life expectancy down the line. An increased level of chronic inflammation is one of the reasons why this is the case, but here is a closer look at another of the mechanisms involved:

Results of this longitudinal study found that people who carry excess weight over their lifetime are much more likely to have increases in left ventricular mass and relative wall thickness - both strong and independent predictors of cardiovascular morbidity and mortality. In this instance, timing is indeed everything; the earlier someone becomes overweight, the greater the increase in the heart's mass later in life.

"Being overweight in your 20s can have detrimental effects on the heart 40 years in the future, especially if you keep the weight on over the years. It's probably the wrong attitude to think 'I know I'm overweight now, but I'll lose the weight later' because the longer you spend overweight, the greater the weight of your heart muscle. And we know from other studies that even if we take away or account for high blood pressure, diabetes or other risk factors for heart disease, somebody with a bigger heart muscle is more likely to have a heart attack, die or have other problems, such as stroke."

Researchers tracked the body mass index (BMI) of 1,653 men and women at different points in their lives to examine the effects of being overweight on the structure of the heart. BMI is a simple measure of the body's fat using a calculation of weight to height. People who were considered overweight, with a BMI of 25 to 29.9, or obese, with a BMI of 30 or above, had the heaviest hearts. [Few], if any, studies have been able to look at this question over such a long duration. He and his team drew from 44 years of data. Strikingly, the heart was 7 percent heavier for those who were overweight beginning in their 20s compared to those who only became overweight in their 60s.

Link: http://www.eurekalert.org/pub_releases/2013-03/acoc-ami030613.php

Tissue engineering of teeth has so far focused on growing new teeth and then implanting them - but you don't necessarily have to produce an exact replacement if you can produce something that works:

Research towards achieving the aim of producing bioengineered teeth - bioteeth - has largely focussed on the generation of immature teeth (teeth primordia) that mimic those in the embryo that can be transplanted as small cell 'pellets' into the adult jaw to develop into functional teeth. Remarkably, despite the very different environments, embryonic teeth primordia can develop normally in the adult mouth and thus if suitable cells can be identified that can be combined in such a way to produce an immature tooth, there is a realistic prospect bioteeth can become a clinical reality.

In this new work, the researchers isolated adult human gum tissue from [patients], grew more of it in the lab, and then combined it with the cells of mice that form teeth. By transplanting this combination of cells into mice the researchers were able to grow hybrid human/mouse teeth containing dentine and enamel, as well as viable roots.

"Epithelial cells derived from adult human gum tissue are capable of responding to tooth inducing signals from embryonic tooth mesenchyme in an appropriate way to contribute to tooth crown and root formation and give rise to relevant differentiated cell types, following in vitro culture. These easily accessible epithelial cells are thus a realistic source for consideration in human biotooth formation. The next major challenge is to identify a way to culture adult human mesenchymal cells to be tooth-inducing, as at the moment we can only make embryonic mesenchymal cells do this."

Link: http://www.sciencedaily.com/releases/2013/03/130308183819.htm

The SENS Research Foundation (SRF) funds research programs aimed at the development of rejuvenation biotechnology - i.e. the basis for medical therapies that can reverse degenerative aging and thus extend healthy, vigorous human life spans. These programs are based on the Strategies for Engineered Negligible Senescence (SENS) first outlined by Aubrey de Grey some years ago. I'm very much in favor of this: the work has to be done, the sooner the better, and the SRF is one of the few places in the world where you can make a donation and know that it's going directly towards high-impact, relevant medical research into human rejuvenation.

I'm pleased to see this sort of thing taking place, for example: a company pledging a percentage of profits to the cause. There has been some discussion of pledging profits and stock in young companies in the past, and rejuvenation biotechnology is popular with the technology entrepreneur community.

Rescue Assist donates to SRF

Rescue Assist, Inc., a company developing a robotic product that readily maneuvers through debris and will help rescue workers find disaster survivors, has pledged 7% of its profits to SENS Research Foundation. Though the corporation was founded only a couple of years ago, it was profitable in 2012, and so has already begun to back SRF and its mission of transforming the way the world researches and treats the diseases of aging. "This is a great example of how entrepreneurs can support our work and our cause," said Dr. Aubrey de Grey, SRF's Chief Science Officer.

"Incorporating a pledge like this at the formation stage of a new company is one of the best ways to support a nonprofit," said Glynn Burke, founder of Rescue Assist. "If this concept can be expanded by others, that would be a fantastic outcome."

You can read the Foundation's annual reports yourself to see how the money is being spent, and how the research and outreach moves forward year by year.

Getting the job done doesn't mean doing it all yourself, however. Completing a demonstration of SENS in mice is sketched in at a decade and a billion dollars if fully funded, but that's the opening scene in a longer play devoted to translating animal studies into human clinical medicine. The point of the SENS Research Foundation is to "completely redefine the way the world researches and treats aging and age-related diseases." Some directly funded research is necessary to this goal, such as when fields are neglected and the research community needs a mix of a kick in the pants and an influx of philanthropic funding - as is the case for work on clearing out advanced glycation end-products from our tissues. But the larger aim is persuasion: persuade a large enough fraction of the research community to agree with with SENS vision of aging, and they will form their own labs and research initiatives to help.

In this sense, SENS is a peaceful revolution of the sort that roll through the world's research communities with some regularity. In a way, SENS has already won its place as the forthcoming dominant paradigm, despite its minority status and tiny budget, and the process of getting to that dominance is all just details. You can tell that this is the case by the way that leaders in the research community are willing to become scientific advisers or host collaborative SENS research programs in their laboratories. Note the signing statement on the SENS Research Foundation advisory board page - it is in essence a refutation of much of what has been dominant in aging research for the past twenty years or so, and important figures in the research community now stand by that view:

Unfortunately, the regenerative medicine approach to combating aging is not yet being adequately pursued by major funding bodies: only a small number of laboratories worldwide are funded (either publicly or privately) to develop therapies that could rejuvenate aged but otherwise undamaged tissues. SRF has risen to the challenge of filling this void in the biomedical research funding arena.

As and when it is developed, this panel of therapies may provide many years, even decades, of additional youthful life to countless millions of people. Those extra years will be free of all age-related diseases, as well as the frailty and susceptibility to infections and falls that the elderly also experience. The alleviation of suffering that will result, and the resulting economic benefits of maintained productivity of the population, are almost incalculable. In our capacity as the overseers of SRF's research strategy, we urge you to do all you can to help SENS Research Foundation carry out this mission with maximum speed.

Once a critical mass of the movers and shakers in a field agree with you, then the rest is history. It might be a lot of work, but it will happen. The latest figure to join the SRF scientific board is a very well known name in the life science community:

SRF's Research Advisory Board Welcomes Dr. George Church

We are honored to welcome Dr. George Church as the newest member of SENS Research Foundation's Research Advisory Board. Our RAB plays a key role in our mission to change the way the world researches and treats age-related disease. By applying expertise from multiple relevant areas, the Board assures that efforts and resources are directed along the most promising avenues.

Dr. Church brings relevant expertise in a number of fields, genetics in particular. He is Professor of Genetics at Harvard Medical School and Director of PersonalGenomes.org, in addition to being the author of the book, Regenesis: How Synthetic Biology Will Reinvent Nature and Ourselves. His 1984 Harvard PhD included the first methods for direct genome sequencing, molecular multiplexing & barcoding, which led to the first commercial genome sequence in 1994.

His innovations in "next generation" genome sequencing and synthesis & cell/tissue engineering resulted in 12 companies spanning fields including medical genomics and synthetic biology as well as new privacy, biosafety & biosecurity policies. He is director of the NIH Center for Excellence in Genomic Science, and his honors include election to NAS & NAE and Franklin Bower Laureate for Achievement in Science.

So on the whole, things are going well, conforming to a progression that will lead to the SENS approach to aging - i.e. build the means of rejuvenation, and do it soon - becoming a large and important force in the medical research community of tomorrow. That is something of a necessary platform to build up the odds of receiving large-scale funding through the usual channels, rather than requiring visionary philanthropists and the crowdfunding efforts of interested communities to open the way.

It is still the case that one small, wealthy group could accelerate that progression by twenty years at this point by funding SENS to the tune of a few hundred million dollars. The odds of the necessary networking happening to create that event will continue to rise with progress in persuading the research community and existing constellation of funding institutions. Life is worth more than money, so the motivation to back rejuvenation research is strong, but people with access to large amounts of money tend to be very conservative in how they deploy it; only the most mainstream of initiatives can hope to be on the inside track for philanthropy. People like Peter Thiel or Dmitry Itskov are not commonplace, sadly.

One of the root causes of aging is the formation of advanced glycation end-products (AGEs), something that happens much faster in a diabetic metabolism, but which nonetheless happens to all of us and causes progressively greater harm as the years pass. AGEs gum together and disable vital protein machinery, and also hammer on cell receptors in ways that cause chronic inflammation and other ills.

Past work on ways to break down AGEs - AGE-breaker drugs - largely occurred prior to the present rapid pace of development in biotechnology, and was both laborious and ultimately of little use in people despite promising animal studies. It turned out that the most important types of AGE in long-lived humans are not the same as in short-lived rodents, and thus drugs that help rats do little for people. However, one single form of human AGE - glucosepane - does make up the vast, overwhelming majority of AGEs in tissues such as skin. So it is a very viable, narrow target now that the research community knows enough to identify it as the primary target.

A safe way to remove glucosepane is needed in order to largely eliminate this contribution to degenerative aging. Sadly, as for much of the foundations of future rejuvenation therapies, little work and funding is directed to this end. This is thus one of the areas in which the SENS Research Foundation hopes to step in and spur greater interest and progress. Here are some notes on the current research programs funded by the Foundation to this end:

Chemical "crosslinking" of the structural proteins of our arteries slowly stiffens them with age, leading to more rigid blood vessels, rising "systolic" blood pressure (the first or top number in a blood pressure reading), and eventually to the loss of the ability of the kidneys to filter toxins from our blood, and a rising risk of stroke with age. Rejuvenation biotechnology can prevent these scourges at their source. New medicines that break apart these molecular "handcuffs" would allow the proteins of the arteries could move freely again, restoring the supple flexibility and cushioning capacity of aging arteries to youthful health and functionality. As a result, damage to the kidneys would be prevented, and strokes averted.

With a generous donation from software entrepreneur Jason Hope, SENS Research Foundation and the Cambridge University Institute of Biotechnology have established a new SENS Research Foundation Laboratory at Cambridge. With no one else taking on this challenging, critical research, the scientists in the Cambridge SENS lab will initiate work on biomedical solutions to glucosepane crosslinks starting from the ground up - with research to develop reagents that can rapidly and specifically detect proteins that have been crosslinked by glucosepane. The development of such reagents is an indispensible enabling technology for the development and testing of candidate glucosepane-breaking drugs.

In parallel, SENS Research Foundation is also providing funding to Dr. David Spiegel's group at Yale University, which has special expertise in making glycation crosslinks and which has recently been studying the mechanisms and chemical vulnerabilities of precursors of glucosepane. Dr. Spiegel's group has also recently published a report clarifying how the first generation crosslink-breaking drug worked. Once the Cambridge SRF lab has successfully established methods for identifying proteins that have been handcuffed together by glucosepane, Dr. Spiegel's group will use them to begin developing potential glucosepane-cleaving agents. Completing the cycle, candidate agents can then be tested at the Cambridge center - initially in tissue culture, and eventually in vivo.

Once developed, any glucosepane-labeling reagents that emerge from the first phase of this work will made available as openly as possible, to accelerate research into the role of crosslinks in disease and aging, and into ways to combat them.

Link: http://www.sens.org/research/research-blog/project-break-aging-arteries-free

The liver is one of the few organs capable of significant regeneration in humans - but even this is more a case of compensatory growth than true regeneration of the sort seen in lower animals. Still, there is probably value in finding out how and why this happens in the liver and not in other organs:

[Researchers have] identified a protein complex that acts as a molecular switch turning on a self-regeneration program in the liver. The protein complex furthermore fine tunes liver metabolism, allowing this to run efficiently in parallel with the tissue damage repair. The new knowledge challenges the current focus on stem cells and may point towards future simplification of treatments used for repairing tissue damage.

"Our new data challenge the predominant 'stem cell-mania' as the results reveal important molecular mechanisms that enable ordinary liver cells to divide and repair tissue damage. This may point to ways of using ordinary liver cells for therapeutic purposes, as these cells may be easier to use than stem cells."

Tissue renewal [is] a job for the stem cells present in our body. One exception is the specialised cells of the liver called hepatocytes. They are responsible for the metabolic functions of the liver, but can at the same time produce new liver cells. "Our results show how a protein complex is changed upon damage to the liver, making it function as a 'switch' turning on a self-renewal program in the hepatocytes. The protein complex literally turns on selected genes that enable division of the hepatocytes, while maintaining their metabolic functions."

The extraordinary ability of the liver cells to divide almost indefinitely resembles the ability of stem cells to self-renew and this finding challenges the current focus on stem cells and stem cell therapy. The new results [are] consistent with new studies of self-renewal in the group of white blood cells called macrophages. "We see a clear overlap in the molecular mechanisms controlling self-renewal in hepatocytes and macrophages and that could indicate the existence of a more general self-renewal program used by specialised cell types. If this is the case, it can really change the current perception that only stem cells are responsible for renewal of our tissues."

Link: http://news.ku.dk/all_news/2013/2013.3/self-repair_of_liver_damage/

Building medical technologies to repair and reverse degenerative aging is one part of a much broader set of transhumanist ideals: aging is only one of many current limits on the human condition that we can work to transcend through applied technology. It is a very important one, far and away the most important one in my opinion, but still one among many. Transhumanism exists as a named brand of thought and vision that some see as being separate from simple common sense about technology (i.e. use it to make things better) because we are moving, quite rapidly, from an age in which we could only crudely change ourselves into an age where the sky is the limit in terms of changing our biology and our minds. To some eyes there is a line in the sand somewhere past our present medical technology and somewhere before being able to regrow limbs, reverse aging, or build artificial intelligences.

Yet I think we've all seen that line shift ever forward as medicine and other technologies advance. Yesterday's uproar over any specific biotechnology is today's acceptance (take stem cell research as a recent line item, for example). It is a grand flaw in the human condition that people fight so much against all that is new, even while taking full advantage of the benefits provided by everything their parents fought against. It's dumb behavior. It slows things down - and in the case of finding ways to treat and ultimately cure degenerative aging, that has a staggering cost in lives and suffering.

With the publicity for a new book on transhumanist thought, I noticed a couple of interviews and articles emerge from the community in recent days. A few links follow, starting with some thoughts on opposition to transhumanist goals. These follow much the same script as opposition to the idea of extending healthy human life; a whole lot of misconceptions and a bunch of stubborn, misplaced idealism.

Common Misconceptions about Transhumanism

Asserting that only death can give life meaning is another bizarre contradiction, and, moreover, a claim that life can have no intrinsic value or meaning qua life. It is sad indeed to think that some people do not see how they could enjoy life, pursue goals, and accumulate values in the absence of the imminent threat of their own oblivion. Clearly, this is a sign of a lack of creativity and appreciation for the wonderful fact that we are alive. I [refute] the premise that death gives motivation and a "sense of urgency" and make the opposite case - that indefinite longevity spurs people to action by making it possible to attain vast benefits over longer timeframes. Indefinite life extension would enable people to consider the longer-term consequences of their actions. On the other hand, in the status quo, death serves as the great de-motivator of meaningful human endeavors.

Humanity and Transcendence

Futurists Samantha Atkins and PJ Manney join Phil and Stephen to discuss whether there is anything truly new in the movement known as "transhumanism." Was there ever a time when humanity wasn't striving to transcend its current state? Perhaps we'll find that we have always lived in the future. If so - how is the situation any different today?

An Interview With David Pearce

David Pearce is a British utilitarian philosopher. He believes and promotes the idea that there exists a strong ethical imperative for humans to work towards the abolition of suffering in all sentient life. His book-length internet manifesto The Hedonistic Imperative outlines how technologies such as genetic engineering, nanotechnology, pharmacology, and neurosurgery could potentially converge to eliminate all forms of unpleasant experience among human and non-human animals, replacing suffering with gradients of well-being, a project he refers to as "paradise engineering".

I have a great deal of sympathy for the Hedonistic Imperative viewpoint. I think that it's importance and relevance to the cultural mainstream will grow alongside progress in the technological capacity to alter the operation of the human brain - though of course it really should be one of the motivations driving a great deal of that progress, the other being the urge to reverse neurodegeneration and sustain the biological infrastructure of the human mind in good health indefinitely.

Mitochondrial damage is important in aging, and a range of evidence suggests it to be perhaps the most important contribution to aging. You might look at the membrane pacemaker theory of aging for example, which points to differences in susceptibility to mitochondrial damage between similar species with divergent life spans, where greater damage resistance correlates to longer life spans.

Mitochondria damage themselves quite readily in the course of the normal operations. They generate the fuel used by other cellular processes, and in the course of doing so also create a flurry of oxidizing compounds - free radicals - that can react with and harm protein machinery. There are natural antioxidant compounds localized to the mitochondria that slow this process down by getting to the free radicals first. Researchers have shown that life span in mice can be extended by boosting the presence of some of these compounds.

It works the other way too; removing or mutating SOD1, one of these antioxidants, shortens mouse life span. Here is an interesting demonstration showing that calorie restriction reverses this effect. That suggests that, while researchers have shown that the benefits of calorie restriction depend on the cellular recycling process of autophagy in some species, the primary mode of operation might be to alter mitochondrial function. Perhaps this occurs through an enhanced autophagic recycling of damaged mitochondria, but other mechanisms are possible:

Dietary restriction is a powerful aging intervention that extends the life span of diverse biological species ranging from yeast to invertebrates to mammals, and it has been argued that the anti-aging action of dietary restriction occurs through reduced oxidative stress/damage. Using Sod1-/- mice, which have previously been shown to have increased levels of oxidative stress associated with a shorter life span and a high incidence of neoplasia, we were able to test directly the ability of dietary restriction to reverse an aging phenotype due to increased oxidative stress/damage.

We found that dietary restriction increased the life span of Sod1-/- mice 30%, returning it to that of wild type, control mice fed ad libitum. Oxidative damage in Sod1-/- mice was markedly reduced by dietary restriction. Analysis of end of life pathology showed that dietary restriction significantly reduced the overall incidence of pathological lesions in the Sod1-/- mice fed the dietary restricted-diet compared to Sod1-/- mice fed ad libitum, including the incidence of lymphoma (27 vs 5%) and overall liver pathology. In addition to reduced incidence of overall and liver specific pathology, the burden and severity of both neoplastic and non-neoplastic lesions was also significantly reduced in the Sod1-/- mice fed the dietary restricted-diet.

These data demonstrate that dietary restriction can significantly attenuate the accelerated aging phenotype observed in Sod1-/- mice that arises from increased oxidative stress/damage.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23459073

Given an easy switch to increase the plasticity of the adult brain, boosting the pace at which new neurons and new neural connections are formed, researchers will gather much more data in the years ahead as to how effective this might be as a stop-gap therapy to slow or compensate for some of the effects of aging:

Scientists have long known that the young and old brains are very different. Adolescent brains are more malleable or plastic, which allows them to learn languages more quickly than adults and speeds recovery from brain injuries. The comparative rigidity of the adult brain results in part from the function of a single gene that slows the rapid change in synaptic connections between neurons.

By monitoring the synapses in living mice over weeks and months, [researchers] have identified the key genetic switch for brain maturation. [The] Nogo Receptor 1 gene is required to suppress high levels of plasticity in the adolescent brain and create the relatively quiescent levels of plasticity in adulthood. In mice without this gene, juvenile levels of brain plasticity persist throughout adulthood. When researchers blocked the function of this gene in old mice, they reset the old brain to adolescent levels of plasticity.

"These are the molecules the brain needs for the transition from adolescence to adulthood. It suggests we can turn back the clock in the adult brain and recover from trauma the way kids recover." Rehabilitation after brain injuries like strokes requires that patients re-learn tasks such as moving a hand. Researchers found that adult mice lacking Nogo Receptor recovered from injury as quickly as adolescent mice and mastered new, complex motor tasks more quickly than adults with the receptor.

Link: http://www.eurekalert.org/pub_releases/2013-03/yu-foa030413.php

A large weight of evidence shows that excess body fat - and specifically excess visceral fat - is bad for you in the long term. Put on weight and your life expectancy drops, even as your lifetime medical costs rise. You will most likely be less healthy for the rest of your life than your leaner peers, and they will outlive you. (Unless of course medical technology advances rapidly enough to save you from the consequences of your diet and lifestyle choices. But that's no certainty; why gamble when you don't have to?)

Some fraction of the consequences of being overweight are actually the consequences of a lack of regular exercise. After all, there is a strong correlation between gaining fat tissue and not exercising, and causal links between the two work both ways. Stop exercising without altering diet, and you'll gain fat tissue. On the flip side of the coin, gain enough fat tissue and exercising becomes much more of a challenge.

Another fraction of the consequences of being overweight stem from the low-level reactions of your metabolism to the overnutrition required to create that excess body fat - the reverse of dietary restriction, but something that is not as well researched at the level of cells and genes, despite the vast real-life population study in overfeeding taking place in much of the world these days. You might note research on harms caused by a dietary excess of methionine, however, methionine being one of the triggers for calorie restriction benefits when dietary intake is reduced. It swings the other way too.

The real monster when it comes to fat tissue and long term health appears to be inflammation, however. Temporary inflammation is a necessary portion of the response to damage and disease by the immune system, but chronic, unremitting inflammation accelerates progress towards frailty and ill-health. Indeed, it shows up as a contributing factor in degenerative aging later in life as the immune system becomes increasingly damaged and erratic. This process is known as inflammaging in some parts of the research community.

Distinct from the aging of the immune system, fat tissue itself spurs chronic inflammation. This has been known for some time, and researchers have been chasing down a detailed explanation as to why this is so. You might look at the connection to macrophage behavior, for example, or cytokine signaling. The more visceral fat you have, the higher your level of chronic inflammation - and thus the more damage gets added per unit time to the state of your biology. Aging itself is nothing more than damage and the reactions of bodily systems to that damage.

Here researchers present a fairly detailed account of how they think fat cells are causing this issue. You might look at the original paper as well as the more digestible research publicity materials linked below:

Obesity makes fat cells act like they're infected

High calorie diets cause [fat] cells to make major histocompatibility complex II, a group of proteins usually expressed to help the immune system fight off viruses and bacteria. In overweight mice and humans the fat cells, or adipocytes, are issuing false distress signals - they are not under attack by pathogens. But this still sends local immune cells into a tizzy, and that causes inflammation.

"We did not know fat cells could instigate the inflammatory response. That's because for a very long time we thought these cells did little else besides store and release energy. But what we have learned is that adipocytes don't just rely on local resident immune cells for protection - they play a very active role in their own defense. And that's not always a good thing."

Could the inflammation caused by a high fat diet serve any purpose, or is it a senseless response to an unnaturally caloric diet?

"The expression of MHCII in adipocytes does not seem to be helpful to the body. It is not at all clear what the advantage would be, given all the negative long-term consequences of fat tissue inflammation in people who are obese, including insulin resistance and, eventually, full diabetes. This just appears to be a runaway immune response to a modern high calorie diet. The bottom line is, you're feeding and feeding these fat cells and they're turning around and biting you back. They're doing the thing they're supposed to do - storing energy - but reacting negatively to too much of it."

[If researchers] can identify the antigen(s) that MHCII is presenting to T cells in fat tissue, medical researchers would have a new approach to target adipose inflammation in obese patients. The hypothesis is that if a treatment can interfere with the production or MHCII presentation of these antigens, this would reduce the activation of fat tissue immune cells and thus reduce inflammation.

With hindsight, it seems that this should be a fairly obvious development. Given that evolution leads to organisms that adjust the operation of their metabolism in response to the prospects for food availability (see calorie restriction and related mechanisms), since that impacts reproductive success and thus evolutionary fitness, then it shouldn't be surprising to find that these organisms also do so based on the prospects for actual reproductive activity.

Aging is associated with compromised hippocampal function and reduced adult neurogenesis in the dentate gyrus. As new neurons have been linked to hippocampal functions, such as cognition, age-related decline in new neuron formation may contribute to impaired hippocampal function.

We investigated whether a rewarding experience known to stimulate neurogenesis in young adult rats, namely sexual experience, would restore new neuron production and hippocampal function in middle-aged rats. Sexual experience enhanced the number of newly generated neurons in the dentate gyrus with both single and repeated exposures in middle-aged rats. Following continuous long-term exposure to sexual experience, cognitive function was improved. However, when a prolonged withdrawal period was introduced between the final mating experience and behavioral testing, the improvements in cognitive function were lost despite the presence of more new neurons.

Taken together, these results suggest that repeated sexual experience can stimulate adult neurogenesis and restore cognitive function in the middle-aged rat as long as the experience persists throughout the testing period. The extent to which changes in adult neurogenesis underlie those in cognition remain unknown.

That said, it is worth noting that almost any environmental enrichment produces the same effect for rats as noted by these researchers, which might say more about the insufficiency of the standard laboratory rat environment than about potential ways to boost neurogenesis in the rest of us.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23460298

We know that removing visceral fat extends life in mice - even a drastic measure such as surgery to remove the fat increases mouse life span. Given that mice are little cancer factories, it shouldn't be surprising to see that at least part of this effect on life expectancy stems from reduced incidence of cancer:

There has been some skepticism as to whether obesity per se is a bona fide cancer risk factor, rather than the habits that fuel it, including a poor diet and a sedentary lifestyle. Although those other lifestyle choices play a role, this study unequivocally demonstrates that visceral adiposity is causally linked to intestinal cancer.

Prior research has shown that obesity markedly increases the likelihood of being diagnosed with and dying from many cancers. [Researchers] sought to determine if removing visceral fat in mice genetically prone to developing colon cancer might prevent or lessen the development of these tumors.

They randomly assigned the mice to one of three groups. Mice in the first group underwent a sham surgery and were allowed to eat an unrestricted "buffet style" diet, for the entirety of the study, which resulted in these mice becoming obese. Those in the second group were also provided an unrestricted diet and became obese, but they had their visceral fat surgically removed at the outset of the study. Mice in the third group also underwent a sham surgery, but were provided only 60 percent of the calories consumed by the other mice in order to reduce their visceral fat by dieting.

"Our sham-operated obese mice had the most visceral fat, developed the greatest number of intestinal tumors, and had the worst overall survival. However, mice that had less visceral fat, either by surgical removal or a calorie-restricted diet, had a reduction in the number of intestinal tumors. This was particularly remarkable in the case of our group where visceral fat was surgically removed, because these mice were still obese, they just had very little abdominal fat."

Link: http://www.eurekalert.org/pub_releases/2013-03/aafc-vfc022813.php

Cells generate all sorts of garbage, the byproducts of metabolism, and also have garbage thrust upon them through a range of mechanisms. Some of the root causes of aging involve forms of garbage that impair the ability to remove garbage - thus leading to the downward spiral that is actually known in the literature as a garbage catastrophe. Diseases like Alzheimer's and Parkinson's are also thought to have a strong component related to the buildup of specific unwanted compounds in and around cells.

The desired approach is to find ways to safely remove garbage. Boosting the ability of cells to do this, through the processes collectively known as autophagy, should be beneficial. The same goes for training immune cells to destroy clumps of unwanted compounds that form between cells. Ultimately, however, some form of biotechnology will be needed to remove those unwanted molecules and structures that autophagy and immune cells don't do well with - such as those that form lipofuscin, a mixed collection of gunk that builds up in long-lived cells and is implicated in a range of different age-related conditions. The SENS Research Foundation works on finding suitable enzymes from soil bacteria to use as a starting point, for example, but there are numerous other potential approaches to building infusions that might break down unwanted garbage in and around cells.

It has to be said that outside of the named diseases that involve aggregates, such as Alzheimer's, there's not a great deal of applied work taking place on this sort of thing. Further, most researchers are more interested in adjusting the underlying mechanisms of cellular metabolism to generate less garbage than in producing a means to periodically clear out garbage. That's pretty much the standard story when it comes to the foundations for rejuvenation biotechnology - not enough is being done to work towards therapies, even though the path ahead is quite clear. Where potentially applicable research is underway, it's slaved to the regulatory structures and restrictions that ensure it will only be used to treat patients suffering end stage diseases of aging, or only takes place in the context of the biology of late-stage disease.

That said, I noticed a couple of recent research publicity releases on the topic of autophagy, garbage, and the degeneration of the brain with aging, and thought I'd point them out.

Age-related dementia may begin with neurons' inability to dispose of unwanted proteins

In research involving both worms and mice, [scientists] have found that age-related dementia is likely the result of a declining ability of neurons to dispose of unwanted aggregated proteins. As protein disposal becomes significantly less efficient with increasing age, the buildup of these unwanted proteins ultimately leads to the development and progression of dementia.

To make this discovery, scientists carried out their experiments in both worm and mouse models that had a genetically-determined dementia in which the disease was caused by protein accumulation in neurons. In the worm model, [researchers] could inactivate distinct routes used for the disposal of the unwanted proteins. Results provided valuable insight into the mechanisms that neurons use to cope with protein accumulation. These pathways were then assessed in young and aged mice. This study provides an explanation of why dementias exponentially increase with age. Additionally, neuron protein disposal methods may offer a therapeutic target for the development of drugs to treat and/or prevent dementias.

Scientists Identify 'Clean-Up' Snafu that Kills Brain Cells in Parkinson's Disease

The most common mutations responsible for the familial form of Parkinson's disease affect a gene called leucine-rich repeat kinase-2 (LRRK2). The mutations cause the LRRK2 gene to code for abnormal versions of the LRRK2 protein. But it hasn't been clear how LRRK2 mutations lead to the defining microscopic sign of Parkinson's: the formation of abnormal protein aggregates inside dopamine-producing nerve cells of the brain.

"Our study found that abnormal forms of LRRK2 protein disrupt an important garbage-disposal process in cells that normally digests and recycles unwanted proteins including one called alpha-synuclein - the main component of those protein aggregates that gunk up nerve cells in Parkinson's patients. We showed that when LRRK2 inhibits chaperone-mediated autophagy, alpha-synuclein doesn't get broken down and instead accumulates to toxic levels in nerve cells."

"We're now looking at ways to enhance the activity of this recycling system to see if we can prevent or delay neuronal death and disease. We've started to analyze some chemical compounds that look very promising."

Researchers here propose that a mechanism associated with age-related cognitive decline is also involved in the poorly understood general declines in vision that occur with age. From the perspective of SENS and aging as damage, this is exactly the sort of thing we'd expect to be a secondary consequence of one of the fundamental changes that drive aging, such as a build up of aggregates or damage to cell mitochondria. Given the complexities of metabolism and cellular operation, the fastest and most efficient way to prove or disprove that - and many similar propositions - is to implement SENS and fix the underlying damage.

Extensive research in the CA1 region of the rat hippocampus has revealed an age-related increase in neuronal Ca2+ influx though L-type voltage-gated calcium channels (L-VGCCs) that is strongly linked with impaired synaptic plasticity and reduced cognitive function.

Diminished visual performance is another important behaviorally-evident functional decline that occurs with aging, beginning in young adulthood, but whose underlying mechanisms are poorly understood. Concurrent declines in neuroretinal function, when measured by electroretinogram (ERG), have also been noted: rod sensitivity and the maximum amplitude of rod responses to light both decrease with age. However, [such] physiological changes were too modest to account for the age-related vision declines. Here, we test an alternative hypothesis: that changes in retinal ion influx via L-VGCCs occur with age, and are linked to visual performance declines.

In Long-Evans rats we find a significant age-related increase in ion flux through retinal L-VGCCs in vivo [that] are longitudinally linked with progressive vision declines. Importantly, the degree of retinal Mn2+ uptake early in adulthood significantly predicted later visual contrast sensitivity declines. Furthermore, as in the aging hippocampus, retinal expression of a drug-insensitive L-VGCC isoform (α1D) increased - a pattern confirmed in vivo by an age-related decline in sensitivity to L-VGCC blockade. These data highlight mechanistic similarities between retinal and hippocampal aging, and raise the possibility of new treatment targets for minimizing vision loss during healthy aging.

Link: http://dx.doi.org/10.1371/journal.pone.0056340

Methionine is an essential amino acid, one that we do not manufacture ourselves but must obtain from what we eat. It seems that a large fraction of the benefits of calorie restriction derive from alterations in metabolism that are based on sensing levels of methionine. Here is a review:

Comparative studies indicate that long-lived mammals have low rates of mitochondrial reactive oxygen species production (mtROSp) and oxidative damage in their mitochondrial DNA (mtDNA). Dietary restriction (DR), around 40%, extends the mean and maximum life span of a wide range of species and lowers mtROSp and oxidative damage to mtDNA, which supports the mitochondrial free radical theory of aging (MFRTA).

Regarding the dietary factor responsible for the life extension effect of DR, neither carbohydrate nor lipid restriction seem to modify maximum longevity. However protein restriction (PR) and methionine restriction (at least 80% MetR) increase maximum lifespan in rats and mice. Interestingly, only 7 weeks of 40% PR (at least in liver) or 40% MetR (in all the studied organs, heart, brain, liver or kidney) are enough to decrease mtROSp and oxidative damage to mtDNA in rats, whereas neither carbohydrate nor lipid restriction change these parameters. In addition, old rats also conserve the capacity to respond to 7 weeks of 40% MetR with these beneficial changes. Most importantly, 40% MetR, differing from what happens during both 40% DR and 80% MetR, does not decrease growth rate and body size of rats.

All the available studies suggest that the decrease in methionine ingestion that occurs during DR is responsible for part of the aging-delaying effect of this intervention likely through the decrease of mtROSp and ensuing DNA damage that it exerts. We conclude that lowering mtROS generation is a conserved mechanism, shared by long-lived species and dietary, protein, and methionine restricted animals, that decreases damage to macromolecules situated near the complex I mtROS generator, especially mtDNA. This would decrease the accumulation rate of somatic mutations in mtDNA and maybe finally also in nuclear DNA.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23454735

Transhumanism is an important movement, even while now somewhat diffused into popular culture in comparison to the online salons of the late 1990s. Why is transhumanism important? Primarily, from my perspective, because a range of the most important present ventures in biotechnology and medicine are informed, supported by, and connected to figures in the transhumanist community. There is cryonics, to pick the most obvious example - and one might argue that modern transhumanism was a offshoot of the cryonics communities and related futurists of the 1960s and 1970s. To pick another example, a great deal of the early funding and enthusiasm for SENS research into the repair of aging, back when it was conducted under the umbrella of the Methuselah Foundation, came from transhumanist circles.

From where I stand, transhumanism is nothing more than common sense about technology and the human condition. We can improve things, so why not improve things? We live in far greater comfort and for more years in good health in comparison to our ancestors precisely because those ancestors created new technologies that change the human condition - lengthening healthy life, removing causes of pain and suffering. As technologies become more sophisticated we have the opportunity to move from such things as defeating smallpox to such things as reliably repairing the cellular and molecular damage that causes aging. These are only matters of degree.

Yet many people, even in this age of constant change, are very much up in arms and threatened by such prospects. It's an odd world we live in, in which folk partake in a wealth of new choices and improvements to their standard of living - things that their parents didn't have - while at the same time decrying efforts to build further improvements for their own children. Rationality is in short supply.

On the topic of transhumanism, let me point you to a forthcoming collection of essays that encompasses many of the important threads of transhumanist thought from the past few decades. When considering where the present scrappy, networked, and diverse community of efforts to extend human life came from, one has to at least read around this subject:

The Transhumanist Reader is first overview of transhumanist thought

The Transhumanist Reader: Classical and Contemporary Essays on the Science, Technology, and Philosophy of the Human Future, edited by Max More and Natasha Vita-More, will be published April 29, 2013.

It is the "first authoritative and comprehensive survey of the origins and current state of transhumanist thinking", according to the editors, and the anthology includes a roster of leaders in transhumanist thought. "The rapid pace of emerging technologies is playing an increasingly important role in overcoming fundamental human limitations," say the editors.

Featuring core writings by seminal thinkers in the speculative possibilities of the posthuman condition, essays address key philosophical arguments for and against human enhancement, explore the inevitability of life extension, and consider possible solutions to the growing issues of social and ethical implications and concerns.

Human life extension, and ultimately the complete defeat of aging, is absolutely an inevitability. No disagreement there. But it is not inevitable that it will occur fast enough for those of us in mid-life today - a great deal of work is yet needed to grow the scrappy, diverse community of initiatives like the SENS Research Foundation into a vast scientific community to rival the cancer research and stem cell research establishments. Whether or not we succeed in this is up to us: unlike the newborns in the audience, most of whom will likely live for centuries, we don't have the luxury of sitting back to let the future come to us.

The longest-lived genetically engineered mice are those in which growth hormone or growth hormone receptors have been diminished or removed entirely. This review looks at some of what is know about the mechanisms involved in this extended life:

Studies in mutant, gene knock-out and transgenic mice have demonstrated that growth hormone (GH) signalling has a major impact on ageing and longevity. Growth hormone-resistant and GH-deficient animals live much longer than their normal siblings, while transgenic mice overexpressing GH are short lived.

Actions of GH in juvenile animals appear to be particularly important for life extension and responsible for various phenotypic characteristics of long-lived hypopituitary mutants. Available evidence indicates that reduced GH signalling is linked to extended longevity by multiple interacting mechanisms including increased stress resistance, reduced growth, altered profiles of cytokines produced by the adipose tissue, and various metabolic adjustments such as enhanced insulin sensitivity, increased oxygen consumption (VO2/g) and reduced respiratory quotient.

The effects of removing visceral fat indicate that increased levels of adiponectin and reduced levels of pro-inflammatory cytokines in GH-resistant mice are responsible for their increased insulin sensitivity. Increased VO2 apparently represents increased energy expenditure for thermogenesis, because VO2 of mutant and normal mice does not differ at thermoneutral temperature.

Recent studies identified GH- and IGF-1-dependent maintenance of bone marrow populations of very small embryonic-like stem cells (VSELs) as another likely mechanism of delayed ageing and increased longevity of GH-deficient and GH-resistant animals. Many of the physiological characteristics of long-lived, GH-related mouse mutants are shared by exceptionally long-lived people and by individuals genetically predisposed to longevity.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23450447

Demonstrations such as the unusual regenerative capacity of MRL mice have bolstered the idea that we mammals retain the vestiges of an ability to regenerate shared with lower animals such as salamanders - but suppressed or buried in some way. Hence work on deciphering the mechanisms of limb and organ regeneration in a variety of species could lead to the ability to turn on similar regeneration in humans. This work casts doubt on that view, however, suggesting that exceptional regeneration is not an ancient process shared across many species:

Tiny and delicate it may be, but the red spotted newt (Notophthalmus viridescens) has tissue-engineering skills that far surpass the most advanced biotechnology labs. The newt can regenerate lost tissue, including heart muscle, components of its central nervous system and even the lens of its eye. Doctors hope that this skill relies on a basic genetic program that is common - albeit often in latent form - to all animals, including mammals, so that they can harness it in regenerative medicine.

Attempts to analyse the genetics of newts in the same way as for humans, mice and flies have so far been hampered by the enormous size of the newt genome, which is ten times larger than our own. [Researchers] therefore looked at the RNA produced when genes are expressed - known as the transcriptome - and used three analytical techniques to compile their data. The team compiled the first catalogue of all the RNA transcripts expressed in N. viridescens, looking at both primary and regenerated tissue in the heart, limbs and eyes of both embryos and larvae.

The researchers found more than 120,000 RNA transcripts, of which they estimate 15,000 code for proteins. Of those, 826 were unique to the newt. What is more, several of those sequences were expressed at different levels in regenerated tissue than in primary tissue. [The] findings add to existing evidence that the ability evolved recently, [such as] evidence that regenerating tissue in salamanders express proteins that are not found in other vertebrates.

"I no longer believe that there is an ancestral program that is waiting to be reawakened. However, I absolutely do believe it's possible to coax mammal tissues into regenerating to a greater degree with the lessons we learn from newts."

Link: http://www.nature.com/news/newt-sequencing-may-set-back-efforts-to-regrow-human-limbs-1.12479

A paper on the life span of neurons in relation to their host organism was published earlier in the year and has been doing the rounds in recent days:

Neurons in mammals do not undergo replicative aging, and, in absence of pathologic conditions, their lifespan is limited only by the maximum lifespan of the organism. Whether neuronal lifespan is determined by the strain-specific lifetime or can be extended beyond this limit is unknown. Here, we transplanted embryonic mouse cerebellar precursors into the developing brain of the longer-living Wistar rats. The donor cells integrated into the rat cerebellum developing into mature neurons while retaining mouse-specific morphometric traits.

In their new environment, the grafted mouse neurons did not die at or before the maximum lifespan of their strain of origin but survived as long as 36 mo, doubling the average lifespan of the donor mice. Thus, the lifespan of neurons is not limited by the maximum lifespan of the donor organism, but continues when transplanted in a longer-living host.

This is indeed the barnstorming age of biotechnology. As you might already know, we humans possess many nervous system cells that we were born with and which will last our entire lifetime. This is in contrast to much of the rest of our body where cells are replaced over various timescales, from years for some tissues to days for others. It is even that case that some individual macromolecules within brain cells last unchanged throughout life - not just the cell remaining on station for a lifetime, but some of its fundamental building blocks as well.

The fact that many neurons are never replaced is the source of a range of frailties and age-related conditions that result from increasing damage or buildup of unwanted metabolic byproducts in these long-lived cells. Nonetheless, it seems very reasonable to expect that our neurons are capable of outlasting the present limits of human life span, given the fact that it isn't neurodegeneration that kills supercentenarians - their brain cells are, by and large, still marching along even in the final years. No, death by aging is a systems failure, not a timed simultaneous failure of all the components that make up that system.

Is work on rodent neurons quoted above particularly relevant, or does it change anything? I is interesting, but I think that the answer is "no." We already know that developing the means to repair existing neurons in the brain is necessary. Boosting the rate at which new neurons are created will almost certainly be helpful, but a good portion of the brain stores the data that is the mind - those neurons and their encoded data have to be preserved and maintained, not replaced wholesale. So here it seems to me that knowing that neurons have a longer shelf-life doesn't change anything in the game plan.

Further, there's no guarantee that the longer neuron shelf-life in rodents has any great relevance to human cells. The analogous human study might be to pull long-lived neurons from a supercentenarian and culture them in a 3-D engineered environment that replicates their home tissue as closely as possible. Then you wait - for a fair number of decades. By the time that experiment comes to any interesting result, the whole issue will be moot. Either we will be dead, or SENS-like rejuvenation biotechnologies will be developed, and in either case researchers will already know so much more about cellular biology that they will be long past the point of answering all the questions that the study might help to resolve.

Calorie restriction produces a general slowing of the progression of degenerative aging and creates sweeping changes at all levels of metabolism. Thus it should not be a surprise to find protective effects no matter how deep you dive into the biochemistry of calorie restricted laboratory animals. Here's one of the many more detailed examples, looking at the abundances of receptors known to be important in brain function:

The effects of aging and long-term caloric restriction, on the regulation of neuropeptide Y (NPY) Y(1), Y(2) and Y(5) receptors subtypes, was studied in 20-month-old male rats fed ad libitum (AL) or submitted to a 40% caloric restriction for 12 months.

In the brain of 3-month-old AL rats, the distribution and densities of Y(1), Y(2) and Y(5) receptors were in agreement with previous reports. In the brain of 20-month-old AL rats, a decrease of NPY receptor subtype densities in regions having important physiological functions such as the cingulate cortex, hippocampus and dentate gyrus, thalamus and hypothalamus was observed.

In contrast, caloric restriction had multiple effects. It induced specific decreases of Y(1)-receptor densities in the dentate gyrus, thalamic and hypothalamic nuclei and lateral hypothalamic area and Y(2)-receptor densities in the suprachiasmatic nucleus of hypothalamus. Moreover, it prevented the age-induced increase in Y(1)-receptor densities in the ventromedial hypothalamic nucleus and decrease in the mediodorsal thalamic nucleus, and increased Y(2)-receptor densities in the CA2 subfield of the hippocampus.

These results indicate that caloric restriction not only counteracts some of the deleterious effects of aging on NPY receptor subtype densities but exerts specific effects of its own. The overall impact of the regulation of NPY receptor subtypes in the brain of old calorie-restricted rats may protect the neural circuits involved in pain, emotions, feeding and memory functions.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23410741

Studies suggest that longer life expectancy runs in families to some degree - though it is always the case that what you get in the genetic lottery can be squandered by poor lifestyle choices. Gene variants appear to be more important in determining remaining life expectancy at older ages than at younger ages, which is another way of saying much the same thing. Either way, the end result will be the same until we can build rejuvenation biotechnology.

According to the findings of some recent studies, the centenarians' offspring appear to represent a promising model for research on longevity and healthy aging. This study compares the health status and the functional status of three groups of subjects: 1. individuals with two long-lived parents (one of whom centenarian), 2. individuals with only one long-lived (centenarian) parent, and 3. individuals with no long-lived parents. The goal is to verify whether the centenarians' offspring display any advantage over the offspring of both non-long-lived parents and to evaluate whether the longevity of the non-centenarian parent provides a further advantage.

A total of 374 subjects (mean age approximately 70 years) was examined. A threshold for longevity was established for non-centenarian parents through demographic data available for Italy (males surviving to at least 81 years of age and females to 87 years). The participants were assessed for their health and functional status by means of a standardized questionnaire and tests of physical performance. Data were analyzed using multivariate regression models adjusted for socio-demographic characteristics and risk factors for age-related pathologies.

The results of the study show that centenarians' offspring have a better functional status, a reduced risk for several age-related pathologies and reduced drug consumption than the offspring of non-long-lived parents. In addition, the health status of centenarians' offspring does not appear to be influenced by the longevity of the second parent. It therefore seems possible to conclude that at ages around 70 years the genetic contribution to health status deriving from having one centenarian parent is not substantially improved if the other parent is also long-lived.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23403041