There is No Overpopulation: Only Waste, Corruption, and Inhumanity

Advocates for rapid and widespread development of engineered longevity are making some progress in dismissing the Tithonus Error - the common and mistaken belief that longevity-enhancing medicine would make a person spend more years as a frail and decrepit elder rather than more years in the prime of life. As more people come to see a future of longevity therapies as personally beneficial, however, a more insidious form of opposition will come to the fore.

By far and away the most common reason I see given these days in opposition to engineered longevity is fear of overpopulation. Environmentalism has become almost a religion in its own right now, and many strands of that religion are essentially death cults: loose networks of like-thinking people who fervently believe, for whatever reasons, that the world is dying, that humans already live too long, and that people should be forced to relinquish technology and return to a simpler era. Extreme fringe variants of the environmentalist death cult really do stand for the complete destruction of humanity, but even supposedly reasonable, middle of the road people are influenced by deathist environmentalism to the point at which it is seen as reasonable to say that (a) too many people exist, and therefore (b) the unending horror, pain, and suffering of death by aging is necessary.

Death cult environmentalism of the "too many people" variety is, fundamentally, a failure of understanding. It is to look at the undeniably bad situations and unpleasant regions of the world and say "this is because too many people are using too many resources," rather than to see that in fact it's all due to misallocation of existing resources and the failure to develop new resources - a grand procession of waste, corruption, and the inhumanity with which human beings treat one another. These situations are problems that can be solved through development and tearing down corrupt systems of rulership - they are not immutable facts of life that must lead to the deaths of millions.

I've spoken of this in the past, so I won't rehash it at great length here:

Overpopulation: Not a Problem Now, and Never Will Be

What some presently view as "overpopulation" is more accurately described as crushing poverty amidst the potential for plenty and resources left unused. This is the result of despotism, corruption, economic ignorance, short-sighted greed and the inhumanity of man unto man - it is not a matter of counting heads. ... Here, then, is a short guide for kleptocrats and egalitarians who want to keep their countries poor. All of these policies have stood the test of time as techniques for creating and maintaining poverty. The list is by no means exhaustive, but it will give would-be political leaders a good idea of how to start their countries on the road to ruin.

Malthusians are Deathists, and Decentralization is the Better Way

And yet, alongside the ethos of human rights and the development of heroic medicine, contemporary society appears estranged from its own humanity. To put it bluntly: it is difficult to celebrate human life in any meaningful way when people - or at least the growth of the number of people - are regarded as the source of the world’s problems. Alongside today’s respect for human life there is the increasingly popular idea that there is too much human life around, and that it is killing the planet. ... today’s Malthusians share all the old prejudices and in addition they harbour a powerful sense of loathing against the human species itself. Is it any surprise, then, that some of them actually celebrate non-existence? The obsession with natural limits distracts society from the far more creative search for solutions to hunger or poverty or lack of resources.

What I do want to direct your attention to, as the 4th Strategies for Engineered Negligible Senescence conference drawns near, is recent work by Leonid Gavrilov and Natalia Gavrilova on demographic models for scenarios of enhanced longevity. For all that everyone and their dog seems willing to stand up in casual conversion and predict Soylent Green the moment that greatly enhanced human life spans are mentioned, there hasn't in fact been much in the way of full-on scientific work done on predicting the demographic results of radical life extension. Over the past year or two the Methuselah Foundation, and now SENS Foundation, have been trying to remedy this state of affairs, and this work by the Gavrilovs is one of the first results of this strategy:

Analysis of already existing computer programs for population projections revealed that many of them are based on short-sighted assumptions of small incremental changes in human life span, and they do not allow making detailed projections for the oldest age groups of the population (which are often collapsed into one single 85+ year category). For this reason, many already existing computer programs of population projections are not well suited for the purpose of this project. Therefore, with the support of the Methuselah/SENS foundation, a new demographic projection software has been developed in this study, which was then validated for consistency of results with traditional approaches. This new demographic software is based on generally accepted cohort-component method of population projections. A number of different demographic projections is considered in this project, assuming several scenarios of life extension.

A general conclusion of this study is that population changes are surprisingly slow in their response to a dramatic life extension. For example, we applied the cohort-component method of population projections to 2005 Swedish population for several scenarios of life extension and a fertility schedule observed in 2005. Even for very long 50-year projection horizon, with the most radical life extension scenario (assuming no aging at all after age 50), the total population increases by 35 percent only (from 9.1 to 13.3 million). Moreover, if some members of the society reject to use new anti-aging technologies for some religious or any other reasons (inconvenience, non-compliance, fear of side effects, costs, etc.), then the total population size may even decrease over time. Thus, even in the case of the most radical life extension scenario, population growth could be relatively slow and may not necessarily lead to overpopulation.

If you're interested in more details, there's a powerpoint version of the SENS conference presentation that can be downloaded from the Gavrilovs' site.

Sadly none of this seems likely to change the minds of those folk emotionally vested in a Malthusian view of the world's ills - they already choose to reject plenty of very straightforward, easily demonstrated forms of data that refute their position. Once more study is just one more study, and removing Malthusianism from its place of great and malicious influence over the minds of billions is likely to be a long struggle.

More on the Heat Shock Response and Life Span

The biochemistry of the heat shock response is connected with enhanced cellular housekeeping and repair, here demonstrated again in nematode worms: "Exposure to mild heat-stress (heat-shock) can significantly increase the life expectancy of the nematode Caenorhabditis elegans. A single heat-shock early in life extends longevity by 20% or more and affects life-long mortality by decreasing initial mortality only; the rate of increase in subsequent mortality (Gompertz component) is unchanged. Repeated mild heat-shocks throughout life have a larger effect on life span than does a single heat-shock early in life. Here, we ask how multiple heat-shocks affect the mortality trajectory in nematodes and find increases of life expectancy of close to 50% and of maximum longevity as well. We examined mortality using large numbers of animals and found that multiple heat-shocks not only decrease initial mortality, but also slow the Gompertz rate of increase in mortality. Thus, multiple heat-shocks have anti-aging hormetic effects and represent an effective approach for modulating aging."


The Research of the 4th SENS Conference

SENS4, the 4th Strategies for Engineered Negligible Senescence conference, is almost upon us: "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." Let me direct your attention to the long list of abstracts for presentation; you'll find a lot of very interesting research in there. For example, the Gavrilovs' examination of demographic changes likely to result from the slowing or reversal of aging: "A common objection against starting a large-scale biomedical war on aging is the fear of catastrophic population consequences (overpopulation). This fear is only exacerbated by the fact that no detailed demographic projections for radical life extension scenario were conducted so far. What would happen with population numbers if aging-related deaths are significantly postponed or even eliminated? Is it possible to have a sustainable population dynamics in a future hypothetical non-aging society? This study explores different demographic scenarios and population projections, in order to clarify what could be the demographic consequences of a successful biomedical war on aging."


The Continuing Search For Human Longevity Genes

This study shows centenarians to more often carry a variant gene that affects exonuclease 1 (EXO1), involved in some forms of DNA repair - adding some fuel to the debate over the significance of nuclear DNA damage in aging. At this stage researchers are turning up longevity-associated differences in genes at a much faster rate than progress in understanding how it all ties together and how important specific genetic differences might be. From the paper: "Human longevity is heritable with a genetic component of 25-32%. Variation in genes regulating the levels of somatic maintenance and DNA repair functions is thought to modulate the aging process and to contribute to survival at advanced age. We tested 92 non-synonymous SNPs in 49 DNA repair genes for a possible association with longevity in a sample of 395 German centenarians and 411 controls. The obtained association signal in exonuclease 1 (EXO1) was further investigated by fine-mapping and mutation detection, leading to the identification of the functionally relevant SNP rs1776180. Our detailed analyses revealed that the common allele (C) of this promoter SNP is significantly enriched in female centenarians. This finding replicated in 455 female French centenarians and 109 controls. ... Given the survival advantage that is associated with the C allele of rs1776180, EXO1 can be considered a candidate for a novel longevity-enabling gene."


An Introduction to the Importance of Autophagy

Autophagy is, put simply, the process by which cells recycle damaged components. Of course like all cellular processes the reality on the ground is anything but simple, and autophagy interacts with all sorts of other processes in ways that can produce counter-intuitive results. But the weight of evidence points to more and better autophagy as beneficial overall, most likely because it leads to fewer lingering damaged components inside a cell. Repeated throughout all your cells, this should result in better functioning tissue, fewer errant biological systems, and a longer life - remember that aging itself is nothing more than accumulated damage and the thrashing of systems trying to adapt to that damage.

I've discussed the importance of autophagy numerous times in the past; you might look at one of the summary posts in the archives, for example. In short:

  • Studies show extension of life span in laboratory animals by increasing autophagy
  • Autophagy is required for calorie restriction to extend life span, and is boosted by the practice of calorie restriction
  • Plausibly, more autophagy might extend life span by more rapidly eliminating damaged mitochondria

In any case, I thought I'd point out a good introduction to the scientific study of autophagy. This is an open access review paper on autophagy in C. elegans, one of the most studied of all species. This species of nematode worm has few cells, doesn't live very long, is cheap to breed and examine, and is very well documented. Despite being a tiny worm, many of its metabolic processes are sufficiently similar to those in mammals that researchers can learn from it - one of the most fortunate accidents of evolution is the degree to which central, longevity-influencing mechanisms of metabolism have been conserved across a vast range of species.

The mechanisms by which autophagy mediates lifespan extension are not yet understood. However, one possibility is that the increase in lifespan is mediated through the autophagy-dependent nonspecific or selective removal of damaged mitochondria, decrease in levels of intracellular reactive oxygen species, and subsequent protection against oxidative damage.

Such a mechanism would overlap with the presumed means by which autophagy may protect against genomic instability and tumor progression. It would also provide a framework for the conceptual integration of the oxidative damage theory of aging and the known stimuli that influence aging through autophagy-dependent mechanisms in C. elegans, including dietary restriction and insulin-like signaling.

Many of the long-lived mutants in C. elegans are resistant to oxidative stress and many mutations that decrease mitochondrial electron transport are long-lived, whereas conversely, mutations that increase oxidative damage shorten lifespan in C. elegans. Thus, longevity in C. elegans (and potentially other organisms) may be mediated either by mutations that directly affect cellular generation or breakdown of reactive oxygen species, or indirectly, decrease reactive oxygen specifies via upregulation of the autophagic turnover of the damaged organelles that generate these harmful species.

Examining the Aged Immune System in Skin

Via ScienceDaily: "We wanted to uncover the workings of skin health in order to see why older people don't deal well with skin infections and are prone to skin cancers also. ... In the past, the reduction in skin health was put down to potential defects in the white blood cells called T-cells that would usually help to identify and clear infection. However, when experiments were carried out with healthy young individuals under the age of 40 years and older individuals over the age of 70 years in this study, it was shown that in fact there is nothing wrong with the T-cells in the older group; instead it is the inability of their skin tissue to attract T-cells where and when they are needed that is the source of reduced immunity. ... Knowing this now raises the question of whether the same defect also occurs in other tissues during ageing. Is it possible that, for example, lung tissues also fail to give out the right message to T-cells to bring them into the tissue to do their job? This may explain, in part, the higher rates of lung cancer, chest infections and pneumonia in older people, perhaps. ... at least in the test tube, it is possible to make older skin express the missing signals that attract T cells. This indicates that, in principle, the defect is entirely reversible."


Linking Inflammation and Insulin Resistance

Excess visceral fat, the insulin resistance of type 2 diabetes and metabolic syndrome, and chronic, damaging inflammation all go together. But why? Looking at the fat tissue tells us that macrophages seem to be involved, but here researchers dive in deeper, finding "in cultured cells and mouse experiments that Fox01 stimulates inflammatory white blood cells called macrophages, which migrate to the liver and adipose, or fat, tissue in insulin-resistant states, to increase production of a cytokine called interleukin-1 beta (IL-1B). The cytokine in turn interferes with insulin signaling. Insulin typically inhibits Fox01, setting up a feedback loop in healthy tissues that helps regulate insulin levels. ... The findings suggest that when there is a lack of insulin or when cells such as macrophages are resistant to its presence, there are no brakes on Fox01's stimulation of IL-1B and its further interference with insulin signaling. That might explain why chronic inflammation often is coupled with obesity and type 2 diabetes." All the more reason to take better care of your health so that you don't find yourself experiencing this firsthand.


The Social Justice View of Longevity Science

The interesting thing about longevity science is that the end result - a much longer, healthier life - is so compelling that even communities traditionally opposed to free and rapid development of new technologies on ideological grounds (such as prioritizing equality so highly that universal poverty and death is preferable to inequality) find their members coming around eventually. See this, for example, from an ethicist steeped in the social justice viewpoint: "A fair system of social cooperation is one that is both rational and reasonable (John Rawls, 2001). Is it rational and reasonable for societies that (1) are vulnerable to diverse risks of morbidity (e.g. cancer, heart disease) and mortality, and (2) are constrained by limited medical resources, to prioritize aging research? In this paper I make the case for answering 'yes' on both accounts. Focusing on a plausible example of an applied gerontological intervention (i.e. an anti-aging pharmaceutical), I argue that the goal of decelerating the rate of human aging would be a more effective strategy for extending the human healthspan than the current strategy of just tackling each specific disease of aging. Furthermore, the aspiration to retard human aging is also a reasonable aspiration, for the principle that underlies it (i.e. the duty to prevent harm) is one that no one could reasonably reject."


Mitochondrial Gene Replacement, Now in Primates

Mitochondria are the cell's power plants, important in the operation of metabolism, how that metabolism determines life span, and many age-related diseases. As described in the mitochondrial free radical theory of aging, a small number of mitochondrial genes are known to be crucial to its operation as the cell's power plant. Damage to those genes is a natural consequence of the operation of a mitochondrion, and leads to a Rube Goldberg sequence of events in which is a healthy cell is turned into a damaged cell that spews forth damaging biochemicals into your body. As those errant cells accumulate, their actions collectively give rise to many of the unwelcome forms of change and damage that come with age: systems failing, organs shutting down, and important biochemical processes running awry because their component molecules are corrupted.

Given all this, we can see that the ability to replace genes in mitochondrial DNA is a foundation for methods of repairing and eliminating this contribution to the aging process. The course of human life suggests that such a working technology would only have to be applied once every few decades.

Of all the branches of potential longevity science, replacement of mitochondrial DNA is one of the most advanced (beyond stem cell research and regenerative medicine of course, which benefits from a far larger research community and funding base). Replacement of all mitochondrial DNA was demonstrated in mice through protofection in 2005, and moving mitochondrial genes into the cell nucleus as an alternative to direct replacement was demonstrated in mice in 2008. That second option is not as simple as you might think in an age of genetic science: copying the gene into the nucleus is a straightforward use of established technology, but that done you still have to manipulate the cell into transporting the proteins produced by that gene back into the mitochondria without breakage. Fortunately, this breakthrough was made, so full steam ahead there.

But back to the straight replacement of entire damaged mitochondrial genomes. Here is a recent report of this goal achieved in primates, though this is a pre-embryonic manipulation performed on a single cell rather than a global change in all the cells of an adult. The point of interest is that it worked and the resulting offspring seem fine; it provides further evidence for the safety of replacing all of a human's mitochondrial DNA (mtDNA):

Mutations in mtDNA contribute to a diverse range of currently incurable human diseases and disorders. To establish preclinical models for new therapeutic approaches, we demonstrate here that the mitochondrial genome can be efficiently replaced in mature non-human primate oocytes (Macaca mulatta) by spindle-chromosomal complex transfer from one egg to an enucleated, mitochondrial-replete egg. The reconstructed oocytes with the mitochondrial replacement were capable of supporting normal fertilization, embryo development and produced healthy offspring.

The underlying technologies are within a few years of completion by the look of it. At that point the real issue becomes one of regulation; the FDA does not permit treatments for aging or changes that happen with aging that have not been lobbied into a designation as an official disease. So any significant progress towards therapies aimed at repairing mitochondrial damage of aging will have to be made outside the regulatory systems of the largest markets. With this science - and many other fields of medicine - so very far ahead of what regulators permit, the breaking point at which large for-profit development groups abandon the system to operate in more permissive regions has to arrive at some near future date.

ResearchBlogging.orgTachibana, M., Sparman, M., Sritanaudomchai, H., Ma, H., Clepper, L., Woodward, J., Li, Y., Ramsey, C., Kolotushkina, O., & Mitalipov, S. (2009). Mitochondrial gene replacement in primate offspring and embryonic stem cells Nature DOI: 10.1038/nature08368

Visceral Fat Versus Liver Fat

By now I'd hope you know that the evidence points to excess visceral fat being very bad for you over the long term. Is it the visceral fat or something else correlated with visceral fat, however? "New findings [suggest] that it's not whether body fat is stored in the belly that affects metabolic risk factors for diabetes, high blood triglycerides and cardiovascular disease, but whether it collects in the liver. ... For years, scientists have noted that where individuals carried body fat influences their metabolic and cardiovascular risk. Increased fat inside the belly, known as visceral fat, is associated with an increased risk of diabetes and heart disease. ... Data from a large number of studies shows that visceral fat is associated with metabolic risk, which has led to the belief that visceral fat might even cause metabolic dysfunction. However, visceral fat tracks closely with liver fat. We have found that excess fat in the liver, not visceral fat, is a key marker of metabolic dysfunction. Visceral fat might simply be an innocent bystander that is associated with liver fat." On the other hand, mouse studies show that surgically removing visceral fat extends life.


More Reprogramming to Create Retinal Cells

Closely following reprogramming of bone marrow cells into retinal cells, researchers have now demonstrated that induced pluripotent stem cells (iPS cells) can turn out retinal cells as well: the scientists have "grown multiple types of retina cells from two types of stem cells - suggesting a future in which damaged retinas could be repaired by cells grown from the patient's own skin. Even sooner, the discovery will lead to laboratory models for studying genetically linked eye conditions, screening new drugs to treat those conditions and understanding the development of the human eye. ... This is an important step forward for us, as it not only confirms that multiple retinal cells can be derived from human iPS cells [but] also shows how similar the process is to normal human retinal development. That is quite remarkable given that the starting cell is so different from a retinal cell and the whole process takes place in a plastic dish. We continue to be amazed at how deep we can probe into these early events and find that they mimic those found in developing retinas. Perhaps this is the way to close the gap between what we know about building a retina in mice, frogs and flies with that of humans."


Immortality Institute Members Debating Its Name Once More

The name of the Immortality Institute is a bold statement - part and parcel of a strategy of shifting the debate about longevity science by planting a flag as far out as possible. It is one and the same with talking about the 1000 or so years an ageless person could expect to live under reasonable assumptions of accident-based mortality rates, or arguing the plausible science behind the complete elimination of aging through ongoing repair strategies. If there is no effort made to plant flags far out in the field and shift the debate, then all that is left are the cautious, institution-bound people whose idea of ambition is to talk about extending life expectancy by seven years - at some fuzzy future date - through working to gently slow down aging.

I, personally, am very much on the side of bold statements and bounds shifting. We won't get more than one chance to build an entirely new research community and see the results it produces in our lifetimes. This is the work of decades. If we don't try to shoot for the moon, then we may as well resign ourselves to those seven extra years and little more, because no-one will be trying to do any better.

But on the other side of the table are those folk who argue that stepping far beyond the present debate in an attempt to shift the playing field will inevitably alienate many people who would otherwise have contributed in some way. That way of looking at things asks whether you'd prefer many people working towards modest goals or a few people working towards ambitious goals.

Over at the Immortality Institute, the members are once again debating the name, this time looking for a compromise position between a name change or no name change. It's one facet of the broader discussion over strategies for advocacy and progress:

ImmInst has always struggled with its name. For some it is a bold, visionary missions statement that sets it apart from the tame mainstream, for others it is a real barrier to engagement and to be taken seriously. Last year, we were on the verge of changing the name in a referendum, but the motion was defeated in the end. We promised those who were disappointed by the outcome that we would revisit the issue this year.

I don’t want to rehearse the same arguments and rerun the same votes - there is a real risk that this would sap all attention and energy from other activities. Instead, the proposal is to acknowledge that each side has a point, that it would be useful if we could use one or the other framework as suitable. So the suggestion is: ImmInst continues to exist and to operate publicly as Immortality institute, but it ALSO trades under other names. This ‘new’ face could be one of the names that people have been using (if those behind those initiatives agree to a merger), or a new name entirely.

The way this could work is that different sub forums have a different banner heading, not the ImmInst banner, certain content pages could have a different heading etc. This is to canvass opinions for a week or so. We are aiming for a final conclusion after the SENS conference.

Head on over and have your say.

Misfolded Proteins Interfere With Heat Shock Response

Protein misfolding is a form of damage that accumulates with age. Here researchers show that some misfolds are more important than others: "Misfolded and damaged proteins spell trouble and are common to all human neurodegenerative diseases and many other age-associated diseases. But when during a lifespan do proteins start to misbehave? A new [study] reports that protein damage can be detected much earlier than we had thought, long before individuals exhibit symptoms. But the study also suggests if we intervene early enough, the damage could be delayed. In studying seven different proteins of the worm C. elegans, the researchers discovered that each protein misfolds at the same point: during early adulthood and long before the animal shows any behavioral, or physiological, change. ... The misfolding coincided with the loss of a critical protective cellular mechanism: the ability to activate the heat shock response, an ancient genetic switch that senses damaged proteins and protects cells by preventing protein misfolding." You might recall that enhanced heat shock response is how SIRT1 is thought to influence health and longevity, and there is a growing interest in manipulating the heat shock response as the basis for longevity and cancer therapies.


Obesity, Demetia, and Shrinking Brains

More on the link between obesity and increased risk of dementia from the New Scientist: "Brain regions key to cognition are smaller in older people who are obese compared with their leaner peers, making their brains look up to 16 years older than their true age. As brain shrinkage is linked to dementia, this adds weight to the suspicion that piling on the pounds may up a person's risk of the brain condition. Previous studies suggested that obesity in middle age increases the risk of dementia decades later, which is accompanied by increased brain shrinkage compared with leaner people. Now brain scans of older people have revealed the areas that are hardest hit, as well as the full extent of brain size differences between obese people and those of average weight. ... High insulin levels and type 2 diabetes tend to accompany being overweight and are risk factors for brain tissue loss and dementia. However, the relationship between brain size and body mass index still stood when the researchers accounted for these conditions, indicating that body fat levels may be linked directly to brain shrinkage. Thompson suggests that as increased body fat ups the chances of having clogged arteries, which can reduce blood and oxygen flow to brain cells."


Working on the Methuselah Foundation Website

As a few of you might know, I've spent the past couple of months rebuilding the Methuselah Foundation web presence and support systems on a quasi-volunteer basis. What's above the waterline and visible to the public is now largely beaten into shape and reinforced with steel rods, set in the form it will occupy going forward.

While I take a break from all that for a little while, it'd be nice to hear what you folk think of the result; does it do it for you? More importantly, it would be helpful to gather outside and unbiased opinions both on what does exist on the website and what might exist in the future - whether in your eyes there are areas of the Foundation website that could be improved or extended. What would you like to see?

Kidney Disease as Accelerated Mitochondrial Aging

Researchers here describe chronic kidney disease as essentially an accelerated form of mitochondrial damage as described in the mitochondrial free radical theory of aging: "Chronic kidney disease (CKD) has been linked to oxidative stress caused by dysregulation of the genes that control mitochondria. A study [has] revealed alterations in respiration gene expression in the white blood cells of CKD patients. ... The researchers found 44 genes that were up-regulated in the peripheral blood mononuclear cells of CKD patients, compared to normal controls. Of these, 11 were genes were involved in the oxidative phosphorylation system. Further tests revealed that the levels reactive oxygen species (ROS) were significantly higher in the CKD group. [Researchers] suggest that these species are part of a vicious circle of respiration dysregulation that ultimately results in CKD ... Our hypothesis is that an increased production of ROS, due to the effect of pro-inflammatory mediators, may cause a profound inhibition of the oxidative phosphorylation system leading to a compensatory 'hypertrophy' of its components. In addition, a hypertrophic and impaired oxidative phosphorylation system may prime a vicious circle, causing a continuous release of ROS."


Biogerontology Research Foundation Funds WILT Study

News from a UK research charity supportive of the Strategies for Engineered Negligible Senescence (SENS): "The Biogerontology Research Foundation in collaboration with the Institute for Biology of Aging funds research in hematopoietic stem cell transplantation in telomerase-knockout mice. Mammals must finely balance stimulation and suppression of cell division: over-permissive cellular proliferation promotes cancer, whereas over-restrictive cell division promotes degeneration. This is especially true in tissues with a high cell turnover, such as the blood. Genetic manipulation of the machinery that maintains the ends of our chromosomes, combined with cell therapy, is potentially a very powerful way to alleviate this problem. However, such an approach is highly complex; as a result, researchers have been reluctant to investigate its components. In this new project, the blood will be used as an example to demonstrate the feasibility of such a manipulation. ... This project will be the first ever test of whether intrinsically mortal stem cells can maintain a proliferating tissue indefinitely if periodically replenished. If the answer is yes, this will motivate exploring such treatments as part of an exceptionally robust cancer-prevention therapy." You will recognize this as an early test of WILT, the SENS strategy for eliminating cancer by destroying its most fundamental required mechanism.


Twelve Longevity Enhancement Methods Demonstrated in Mice

Researchers have discovered a large - and continually growing - number of ways to significantly extend healthy and maximum life span in mice. Here I'll list a selection of twelve of the most interesting methods I've seen in past years. Note that I'm omitting a number of studies that show only small (less than 10%) increases in maximum mouse life span, and also leaving out some work in progress that looks likely to enhance life span. For example, Cuervo's work on enhancing autophagy where we're waiting on formal publication of mortality rate data, or enhanced uncoupling protein studies that show median life span increases but not maximum life span increases.

But on with the list:

1) Calorie Restriction, Intermittent Fasting, and Methionine Restriction

Imposition of calorie restriction in mice has been shown to extend life span by around 40% even when initiated comparatively late in life. See for example, the study that is the present rejuvenation Mprize winner:

Here we demonstrate that CR initiated in 19-month-old mice begins within 2 months to increase the mean time to death by 42% and increase mean and maximum lifespans by 4.7 and 6.0 months, respectively. The rate of age-associated mortality was decreased 3.1-fold.

Intermittent fasting, such as alternate day fasting, results in similarly low calorie intake and noteworthy extension of life span, but there is some evidence to think that it operates via a different (though probably overlapping) set of biological mechanisms to calorie restriction.

Methionine restriction has recently come to be more interesting as researchers search for the biological triggers that produce health and longevity benefits in response to calorie restriction. One candidate is the response to the level of methionine, one of the essential amino acids. Diets artificially low in methionine produce extended longevity in mice, though not to the same extent as calorie restriction:

Life span can be extended in rodents by restricting food availability (caloric restriction [CR]) or by providing food low in methionine (Meth-R). Here, we show that a period of food restriction limited to the first 20 days of life, via a 50% enlargement of litter size, shows extended median and maximal life span relative to mice from normal sized litters and that a Meth-R diet initiated at 12 months of age also significantly increases longevity.

2) Growth Hormone Knockout, IGF-1 and Insulin Signalling Manipulation

A breed of dwarf mouse that entirely lacks growth hormone is the present winner of the Mprize for longevity, living 60-70% longer than the compeition's standard laboratory mouse species. This is primarily interesting as a demonstration that insulin signalling and IGF-1 - intimately bound up with growth hormone - are very important to the operations of metabolism that determine life span. These dwarf mice are not very robust: whilst healthy and active, they wouldn't survive outside the laboratory or without good care due to their low body temperature.

You might look at this post from the archives for an introduction to present thinking on IGF-1 and insulin in longevity and metabolism:

insulin and insulin-like growth factor-1 (IGF-1)-like signaling and its downstream intracellular signaling molecules have been shown to be associated with lifespan in fruit flies and nematodes. More recently, mammalian models with reduced growth hormone (GH) and/or IGF-1 signaling have also been shown to have extended lifespans as compared to control siblings. Importantly, this research has also shown that these genetic alterations can keep the animals healthy and disease-free for longer periods and can alleviate specific age-related pathologies similar to what is observed for [calorie restricted] individuals. Thus, these mutations may not only extend lifespan but may also improve healthspan, the general health and quality of life of an organism as it ages.

3) Telomerase Plus p53

A Spanish group published a study in 2008 showing 50% life extension in mice by a suitable combination of enhanced telomerase and p53. The enzyme telomerase extends telomere length thus prolonging the life of individual cells - which usually leads to cancer rather than extended life. p53 on the other hand is an anti-cancer gene that normally reduces life span whilst lowering the risk of cancer - the traditional view being that mechanisms of extended longevity and mechanisms of cancer resistance have evolved to a point of balance. We enterprising humans can always improve on the end results of evolution, however (even if we can't yet manage a decent automated transation of Spanish to English):

So it seems necessary to ask the molecular biologist if, in this battle that they have undertaken jointly against the cancer and the aging, it is only a question of putting telomerase into a mouse to make it immortal. "The answer is no, because telomerase causes more cancer. So that there is a tumor, it must activate telomerase, and if a mouse has more telomerase than the normal thing, for example, making transgenic mice, we know that it will have more tumors. What we have done is to use the Manuel [Serrano's] supermice, because p53 protects against cancer and extends life of the mice 18%, and added the gene of immortality, telomerase, and we obtained that these multitransgenic mice live an average on a 50% more, without cancer.

4) Inactivating the CLK-1 Gene

Reducing the activity of the mitochondria-associated gene clk-1 - lowering the amount of protein generated from its blueprint in other words - boosts mouse longevity by 30% or so. This may be one of the many interventions to work through its effects on mitochondria, the cell's power plants. As we know, mitochondria are very important in aging.

The longevity-promoting effect of reducing CLK-1 activity that was initially observed in C. elegans is conserved in three different genetic backgrounds of mice. In 129Sv/JxBalb/c mice for instance, reducing activity of the gene mclk1 (mouse clk-1) results in a prolongation of lifespan of about 32%. The inactivation of mclk1 gene, which encodes a mitochondrial enzyme, decreases reactive oxygen species (ROS) levels, the toxic molecules that damage proteins, lipids and DNA, and this likely explains this increase in lifespan.

5) SkQ, a Mitochondrially Targeted Ingested Antioxidant

A Russian researcher has demonstrated a form of antioxidant that can be targeted to the mitochondria even though ingested. Per the mitochondrial free radical theory of aging, anything that can reduce the damage mitochondria do to themselves via the free radicals they generate in the course of their operation should extend life span. Indeed, SkQ seems to boost mouse life span by about 30%:

The life time of [SkQ ingesting] mice increased by one third on average as compared to that of the reference group mice. Even more demonstrative are experiments with mutant rats, where accelerated ageing - progeria - was observed. SkQ prolonged their life span by three times, besides, it cured them from a large number of senile diseases. They include infarctions, strokes, osteoporosis, hemogram abnomality, reproductive system disorders, behavior change, visual impairment.

6) Genetic Manipulation to Target Catalase to the Mitochondria

A couple of research groups have shown that through either gene therapy or genetic engineering the levels of a naturally produced antioxidant catalase can be increased in the mitochondria. This increases mouse life span, presumably by soaking up some portion of the free radicals produced by mitochondria before they can cause damage. See this for example:

Earlier studies have found that mice would live longer when their genome was altered to carry a gene known as mitochondria-targeted catalase gene, or MCAT. However, such approaches would not be applicable to human. Duan and Dejia Li [took] a different approach and placed the MCAT gene inside a benign virus and injected the virus into the mice. Once injected, Duan and Li tested the mice and found that they could run farther, faster and longer than mice of the same age and sex.

As well as the original work by Rabinovitch:

The mice lived 20 percent longer than normal mice - on average they lived five and a half months longer than the control animals, whose average life span was about two years.

7) Genetic deletion of pregnancy-associated plasma protein A (PAPP-A)

This is another method of reducing cancer incidence and also extending life span by 30% or so, but this time seemingly through manipulation of the insulin signalling system in a more subtle way than previous growth hormone knockout studies. The end results certainly look like a win-win situation: extended life span and less cancer with no downside.

Genetic deletion in mice of pregnancy-associated plasma protein A (PAPP-A), a recently identified metalloproteinase in the insulin-like growth factor system, extends by 30-40% both mean and maximum lifespan with no reduction in food intake or secondary endocrine abnormalities. Furthermore, these mice have markedly reduced incidence of spontaneous tumors. The findings implicate PAPP-A as a critical regulator of lifespan and age-related diseases, and suggest PAPP-A as a possible target to promote longevity.

By now you should be quite convinced that evolution has not optimized for longevity in species like the common mouse. That any number of comparatively simple genetic manipulations or mutations exist to give what appear to be unqualified benefits to longevity and health is an apt demonstration of this fact.

8) Knockout of the adenylyl cyclase type 5 (AC5) gene

Mice lacking the gene for the AC5 protein, which strangely enough appears to be a crucial component of the opioid response in mammals in addition to its other roles, live 30% longer. This is suggested to be due to a more aggressive, effective repair and prevention response to oxidative damage.

The new discovery, that knocking out a single cardiac gene could lengthen lifespan, was an unexpected byproduct of heart research. ... mutant mice lacking [the gene for protein] AC5 were more resistant to heart failure caused by pressure within the heart. But in the process, the research team also realised that the mutant mice lived longer than their normal counterparts. [Now] they report that the treated mice lived 30% longer and did not develop the heart stress and bone deterioration that often accompanies ageing.

9) Metformin used as a calorie restriction mimetic drug

The drug metformin has been demonstrated to act in some ways like calorie restriction in mouse biochemistry, producing a modest 10% gain in maximum life span.

Here we show the chronic treatment of female outbred SHR mice with metformin (100 mg/kg in drinking water) slightly modified the food consumption but decreased the body weight after the age of 20 months, slowed down the age-related switch-off of estrous function, increased mean life span by 37.8%, mean life span of last 10% survivors by 20.8%, and maximum life span by 2.8 months (+10.3%) in comparison with control mice.

The present pharmaceutical industry search for commercial calorie restriction mimetic drugs is heated and likely to expand in future years, moving out beyond CR metabolism and into anything else where some link can be demonstrated between gene, designer drug, and longevity in mice.

10) FIRKO, or fat-specific insulin receptor knock-out mice

FIRKO mice have less visceral body fat than normal mice, even while eating at the same calorie levels. They live a little less than 20% longer, and this is taken as one line of evidence to show that that possessing a lot of visceral fat is not good for longevity.

Both male and female FIRKO mice were found to have an increase in mean life-span of ~134 days (18%), with parallel increases in median and maximum life-spans. ... Together, these data suggest that maintenance of mitochondrial activity and metabolic rates in adipose tissue may be important contributors to the increased lifespan of the FIRKO mouse.

11) Removal of visceral fat by surgery

Continuing the fat theme, researchers demonstrated last year that you can extend the life span of mice by surgically removing excess visceral fat. It doesn't extend life as much as calorie restriction, but it is significant:

We prospectively studied lifespan in 3 groups of rats: ad libitum fed (AL), 40% caloric restriction (CR) and a group of ad libitum fed rats with selective removal of VF at 5 months of age (VF-). We demonstrate that compared to AL, VF- rats had a significant increase in mean and maximum lifespan and significant reduction in the incidence of severe renal disease.

CR animals demonstrated the greatest mean and maximum lifespan the lowest hazard rate of death as compared to AL rats. Taken together, these observations provide the most direct evidence to date that a reduction in fat mass, and specifically VF, may be one of the possible underlying mechanisms of the anti-aging effect of CR.

You'll find quite a lot in the Fight Aging! and Longevity Meme archives on the mechanisms by which fat is thought to harm long term health and cause low-level damage throughout the body. You might start with these:

12) Overexpression of PEPCK-C, or phosphoenolpyruvate carboxykinase

In this case, researchers have no firm conclusion as to why and how this genetic manipulation works. As in a number of other cases, this investigation wasn't started as a part of any aging or longevity study, and the longevity of these mice is a fortunate happenstance. Nonetheless, here we have a case of what appears to be a more than 50% life extension - though note that the formal life span study has not been published, so you might assume the comments below to refer to the outliers amongst these mice rather than the average.

These mice were seven times more active in their cages than controls. On a mouse treadmill, PEPCK-C mice ran up to 6 km at a speed of 20 m/min while controls stopped at 0.2 km. ... The PEPCK-C mice eat 60% more than controls, but had half the body weight and 10% the body fat ... In addition, the number of mitochondria and the content of triglyceride in the skeletal muscle of PEPCK-C mice was greatly increased as compared to controls. PEPCK-C mice had an extended life span relative to control animals; mice up to an age of 2.5 years ran twice as fast as 6-12 month old control animals. ... they lived almost two years longer than the controls and had normal litters of pups at 30 to 35 months of age (most mice stop being reproductively active at 12 to 18 months).

The full paper, complete with Bruce Springsteen quote, is freely available at PubMedCentral. It outlines the tentative theories of the researchers as to how these mice fit in to present theories of aging and other known longevity manipulations.

We suspect that the major factor responsible for the longevity of the PEPCK-Cmus mice is the very low concentration of insulin in the blood of the mice that is maintained over their lifetime of hyperactivity.

Enhanced Longevity: When Is It Real, and How Can We Be Sure

Via the Gerontology Research Group mailing list, my attention was directed to the upcoming 2009 San Antonio Nathan Shock Conference on Aging:

Lifespan/Healthspan Extension in Aging Research: When Is It Real and How Can We Be Certain?

Conference Dates: October 15 - 18, 2009
Conference Location: Mayan Ranch, Texas Hill Country, Bandera, Texas

A look at the PDF program will show you that researcher Peter Rabinovitch is amongst the speakers with a talk entitled "Lifespan Extension by Catalase Overexpression: Here, Gone, and Back Again…". You might recall that he is one of those to have demonstrated a significant increase in mouse life span by targeting an antioxidant - the naturally produced catalase in this case - to the mitochondria. Others in this select group include Skulachev, associated with the Russian Science Against Aging initiative, and some folk at the University of Missouri who used a different approach to Rabinovitch but also increased catalase in the mitochondria.

The interesting question is why this works while generally increasing catalase - or indeed any other type of antioxidant - without specifically targeting mitochondria has no effect or even detrimental effects on life span. This is no doubt related to the importance of mitochondrial damage in degenerative aging.

Scientists generally concur that accumulated damage throughout the body due to free radicals is one important root cause of age-related degeneration - but the devil is in the details. The vast, overwhelming majority of those free radicals are generated by your own [mitochondria] as an unavoidable byproduct. The rate of free radical generation increases greatly with age as the basic mechanisms of your of [mitochondria] are themselves damaged by the free radicals they created.

But back to considering the conference: you should also recognize many of the other speakers from the gerontology community. It looks like being an interesting event.

The End of Aging: an Evening With Aubrey de Grey

Here is something for those of you who will be in the New York area this time next month: "The Singularity Institute for Artificial Intelligence is co-sponsoring a program on ending aging with gerontology researcher Aubrey de Grey and the New York Academy of Sciences, on the evening of Tuesday, September 22nd in New York City. ... Could it be possible for humans to live hundreds of years in the very near future? Is aging a curable disease? Iconoclast Aubrey de Grey predicts it's only a matter of decades before regenerative medicine extends human life expectancy indefinitely. This event is one of five events in the 2009 Provocative Thinkers Series presented by Science & the City, a program of the New York Academy of Sciences. Cosponsored by the Singularity Institute." A large number of de Grey's past presentations to groups large and small can be found at YouTube - you might want to take a look.


Trends in Miniaturization of Functional Organ Replacements

A dialysis machine, intended to replace the function of damaged kidneys, might weigh 55kg. Researchers now have that down to 5kg in a wearable form, a machine which does a better job to boot. Looking ahead, we'd expect even more effective implants or bracelets worn over surface veins in the 2020s - essentially viable artificial replacements for the function of an organ. This is an important trend to watch, as I believe it will ultimately contribute to enhanced longevity just as greatly as regenerative medicine: "Our vision of a technological breakthrough has materialized in the form of a Wearable Artificial Kidney, which provides continuous dialysis 24 hours a day, seven days a week ... The device - essentially a miniaturized dialysis machine, worn as a belt - weighs about 10 pounds and is powered by two nine-volt batteries. Because patients don't need to be hooked up to a full-size dialysis machine, they are free to walk, work, or sleep while undergoing continuous, gentle dialysis that more closely approximates normal kidney function. ... We believe that the Wearable Artificial Kidney will not only reduce the mortality and misery of dialysis patients, but will also result in significant reduction in the cost of providing viable health care."


The Far Reaches of Hypothetical Dietary Design

Based on recent research, it seems to be the case that the operation of calorie restriction in laboratory-bred flies is as dependent on what a fly senses as what it eats. See this review for example:

Could the mere perception of food availability reverse the beneficial effects of diet restriction, which robustly increases lifespan and reduces aging-related disease in many species? We had noted from previous work in Drosophila that the effects of dietary restriction were fast acting, completely reversible, and largely independent of the energetic content of the food. Indeed, some characteristic of the diet seemed to be "sensed" by the flies independent of their tendency to eat it. We quickly realized that the Drosophila olfactory system, with its well-understood architecture and associated set of genetic tools, was the ideal model to test our hypothesis. Subsequent work resulted in the identification of particular odorants and populations of sensory neurons with potent effects on lifespan, obesity, and metabolism.

From there one would hypothesize that a diet for flies could be constructed that doesn't use methionine or protein restriction to trigger calorie restriction benefits, yet nonetheless extends life span and enhances health through use or avoidance of specific scents.

Then we might ponder, completely speculatively, whether primates have inherited any such sensitivity to specific scents as part of our evolutionary heritage. There is no evidence to suggest that we have, but it is nonetheless interesting to postulate a scent-based array of possible ways to build a diet that is rich in calories but still triggers some form of positive calorie restriction biochemistry.

Meanwhile, feet back on the ground, the strong evidence for the benefits of methionine restriction in mammals is a fairly direct pointer to a way to engineer a diet that will produce health benefits without adopting a calorie restriction lifestyle. I continue to be surprised that no elements within the "anti-aging" marketplace are pursuing this sort of product development; given the financial success and public awareness of branded dietary products, you'd think this would be right up their alley.

ResearchBlogging.orgPletcher, S. (2009). The Modulation of Lifespan by Perceptual Systems Annals of the New York Academy of Sciences, 1170 (1), 693-697 DOI: 10.1111/j.1749-6632.2009.04926.x

Catalase in the Mitochondria Via Virus

Mitochondrially-targeted antioxidants - such as catalase - have been shown to extend life span in mice. Here is a method of using catalase that employs a viral vector: "Earlier studies have found that mice would live longer when their genome was altered to carry a gene known as mitochondria-targeted catalase gene, or MCAT. However, such approaches would not be applicable to human. Duan and Dejia Li [took] a different approach and placed the MCAT gene inside a benign virus and injected the virus into the mice. Once injected, Duan and Li tested the mice and found that they could run farther, faster and longer than mice of the same age and sex. Duan attributes this performance enhancement to the MCAT and believes the gene is responsible for removing toxic substances, known as free radicals, from the mitochondria, the powerhouse of the cell. By using this specific gene therapy vector, the virus, to introduce the longevity gene, Duan and Li opened the possibility of human treatment. ... Our results suggest similar therapy may one day improve the life quality of the elderly. This could have important implications for many diseases, such as muscular dystrophy, heart disease, diabetes and neurodegenerative diseases. These patients typically have too many toxic free radicals in their cells."


Like Clockwork

Mainstream press articles on increasing life expectancy arrive on a schedule like clockwork: "U.S. life expectancy has risen to a new high, now standing at nearly 78 years ... The increase is due mainly to falling death rates in almost all the leading causes of death. The average life expectancy for babies born in 2007 is nearly three months greater than for children born in 2006. ... Life expectancy is the period a child born in 2007 is expected to live, assuming mortality trends stay constant. U.S. life expectancy has grown nearly one and a half years in the past decade, and is now at an all-time-high. ... Japan has the longest life expectancy - 83 years for children born in 2007, according to the World Health Organization. The CDC report found that the number of deaths and the overall death rate dropped from 2006 - to about 760 deaths per 100,000 people from about 776. The death rate has been falling for eight straight years, and is half of what it was 60 years ago. Heart disease and cancer together are the cause of nearly half of U.S. fatalities. The death rate from heart disease dropped nearly 5 percent in 2007, and the cancer death rate fell nearly 2 percent, according to the report." Life expectancy is a statistical construct that looks back into the past to measure trends; it doesn't actually have anything to say about how long people born today are likely to live. This, after all, is an era of great change and progress in biotechnology.


The A4M Version of the Longevity Dividend

I see that the American Academy for Anti-Aging Medicine (A4M), owner of the World Health Network and organizer of conferences for the "anti-aging" marketplace, has published what immediately strikes me as being their take on - or response to - the Longevity Dividend initiative. You might want to look back in the Fight Aging! archives for some background on A4M before continuing:

A Look at the World Health Network

The World Health Network is the online face of the American Academy for Anti-Aging Medicine (A4M), yet another of the predominantly old school organizations in the wider healthy life extension community that leave me with mixed opinions. I have been watching A4M beat their online presence - a website with a respectable Alexa traffic rank of 52,000 or so - into shape over the past few years. Over that time, the face of A4M as represented by their website - and interviews with the founders in the mainstream media - has evolved to present a much more forward-looking, responsible perspective. Less hormone therapy and supplements, more stem cells, genetics, and modern medical research.


As I've said before, A4M says a lot of the right stuff and their hearts do appear to be in the right place - it's their implementation that leaves much to be desired.

On the A4M Anti-Aging Conferences

The A4M Chicago conference later this month is, like the recent Singapore event, is very much a collision between the best and worst that business, activism and science has to offer on the topic of intervening in the aging process.


The enthusiasm of the A4M founders for extending the healthy human life span is admirable, but in the process of becoming poster boys and promoters by proxy for skin cream and exercise machines, this message gets lost. People look at "anti-aging medicine" and see scams and nonsense, a state of affairs that is entirely the fault of elements within the marketplace

On to the A4M presentation and white paper, now that you are better placed to judge whether you want to pay any attention to it:

We unveil an innovative, technology-based fix to healthcare with the potential to [increase] the lifespan, or improve the healthspan, of all Americans by 29+ years; slash healthcare costs, saving $3.7 Trillion; and replace the disease-based approach to medicine with a wellness-oriented model.


The A4M Twelve-Point Actionable Healthcare Plan: A Blueprint for A Low Cost, High Yield Wellness Model of Healthcare by 2012 provides the following practicable "here and now" solutions to reform and advance healthcare in the United States, while addressing the challenges of global aging

Now regardless of your thoughts on the content or the nature of the messenger - and as for many of these things there's some sanity and good sense mixed in there if you want to dive in and look for it - this seems very much to me like a vote of confidence in the Longevity Dividend. The folk at A4M believe that the Longevity Dividend - or something very much like it - will succeed in redirecting a significant amount of government funding towards applied aging research. You'll recall that the Longevity Dividend itself is essentially a proposal for how to spend public funds on medical research and development to slow the aging process. Spending without end, limit, or sense of consequence is in the air, it seems, and groups are looking at how best to position themselves before the trough in their particular neck of the woods is filled.

Given the zeitgeist, more public funding for anything and everything that has political pull seems likely. It will be interesting to see - in that watching an avalanche roaring down the slope towards you sort of way - exactly how these particular tumbling rocks fall. Are these unfolding political efforts a fair proxy for the evolving opinions of the masses in regard to longevity science or not? If they are, then we may see a promising evolution of distributed efforts in aging-related biotechnology development in the years ahead as costs fall - distributed efforts that should be somewhat protected from whatever economic disasters are being set up by present policies.

Superlongevity, Superintelligence, Superabundance

From Accelerating Future, thoughts on goals: "Superlongevity, superintelligence, and superabundance are a perfect summary of what we want and need. How can we achieve them? Superlongevity can be achieved by uncovering the underlying mechanisms of aging and counteracting them at the molecular level faster than they can cause damage. Huge research project, a long-term effort, but definitely worth the time and money. Leading organization in this area? The SENS Foundation. Superintelligence will be a difficult challenge, creating an intelligent being smarter than humans in every domain. It could take decades, or possibly longer, but it does seem possible. ... Superabundance can be achieved by creating programmable self-replicating machines powered and supplied by easily available resources and materials ... Achieving superlongevity, superintelligence, and superabundance will be incredibly challenging, but seemingly inevitable as long as civilization continues to progress ... There is no guarantee that we will achieve these goals in our lifetime - but why not try? Achieving any of these milestones would radically improve quality of life for everyone on Earth. The first step to making technological advancements available to everyone is to make them available for someone."


Seeking an Application of Klotho

Researchers are looking for ways to apply knowledge of the longevity gene klotho for medical benefit: "A newly-discovered anti-aging gene could be manipulated to stop or even prevent high blood pressure, a leading contributor to early death ... Persistent high blood pressure, also called hypertension, can lead to stroke, heart attacks and kidney failure. About one-third of Americans struggle with the condition ... an anti-aging gene called klotho decreases as humans age while hypertension tends to increase. Increasing the expression or output of the gene in lab animals reduced blood pressure and reversed kidney damage from hypertension.
Sun said testing on humans is the next step, and it would be years before a therapy could be sold. ... All of us will be and should be extremely hopeful this can occur. ... it's possible the therapy could protect other organs - such as the brain and eyes - from conditions related to aging." This is all pretty speculative beyond the fact of the animal study results - and for most people lifestyle conditions like hypertension are very avoidable. Lead a fat, sedentary life, and don't be surprised when your body starts to fail more rapidly than those who kept fit or practiced calorie restriction.


Fundraising Success For Laser Ablation of Lipofuscin

The good news for today is that the longevity science grassroots centered at the Immortality Institute have successfully raised $8,000 to fund research into laser ablation of lipofuscin. Those funds will be matched up to $16,000 at the SENS Foundation and put towards work on a method of eliminating one form of damaging metabolic byproducts that build up with age:

Lipofucsin is an aggregate of many different biochemical byproducts that builds up in your longest-lived cells, leading to dysfunction and disease. Lipofuscin levels are a very straightforward difference between old and young people, and removing it at regular intervals should have a noticeable impact on age-related degeneration. This is in fact an aspect of one of the seven avenues of Strategies for Engineered Negligible Senescence (SENS) research - removing damaging aggregates from the body.


Mr. Schooler has conducted preliminary qualitative research using laser pulses to destroy lipofuscin in nematodes (round worms). VIDEO HERE. This investigation was the subject of a presentation at the UABBA conference at UCLA in 2008. The current proposed research will use various pulsed laser treatments to investigate the effects on worm lifespan. Human cell culture models will also be used to investigate the dynamics of lipofuscin destruction microscopically in actual human cells.

The fundraising deadline was yesterday, Monday 17th, and as is so often the case in these efforts, racing against the clock proved to be very focusing. Congratulations are due to the volunteers and advocates who managed the fundraising efforts. This sort of thing is a great model for the future of biotechnology, in which important proof of concept research becomes so cheap - indeed, has already become so cheap - that it can be funded in this manner.

From the Immortality Institute forum thread on the fundraising initiative:

It will take a couple days to get the exact accounting of the amount donated. Then Imminst will cut a check to [the SENS Foundation, who will be managing the actual research project]. Nason [Schooler] has already begun preparations for full blown experiments and expects to keep us up to date when things start in earnest. So things are already set-up and should get going in about a week or two.

Growing New Coronary Arteries

Scientists continue to experiment successfully with the use of stem cells to engineer regeneration: "researchers have identified stem cells that are able to grow new coronary arteries, a finding that could lead to new ways to treat atherosclerosis. ... We have defined this novel class of primitive cells and named them coronary vascular progenitor cells [CVPCs]. These cells possess all of the fundamental properties of stem cells and are distributed within niches located in the vessel wall of the entire human coronary circulation system. ... To test the activity of these cells, the scientists created a blockage in a coronary artery in dogs and injected human CVPCs in the blocked artery. After one month, the dogs showed improvements in blood flow and heart functioning. The researchers found that the dogs had grown large, intermediate and small human coronary arteries. ... The findings suggest that the human heart contains a reservoir of CVPCs that can be used to create a biological bypass in patients with chronic coronary artery disease and ischemic cardiomyopathy, which results when arteries that supply blood and oxygen to the heart are blocked."


A View of Longevity Science From the Mainstream

To the man in the street and mainstream journalism, medical science is nothing more than drug development - an unfortunate and blinkered viewpoint. Here is that viewpoint turned to regard research into metabolic manipulation to slow aging: "It may be the ultimate free lunch - how to reap all the advantages of a calorically restricted diet, including freedom from disease and an extended healthy life span, without eating one fewer calorie. Just take a drug that tricks the body into thinking it's on such a diet. It sounds too good to be true, and maybe it is. Yet such drugs are now in clinical trials. Even if they should fail, as most candidate drugs do, their development represents a new optimism among research biologists that aging is not immutable, that the body has resources that can be mobilized into resisting disease and averting the adversities of old age. This optimism, however, is not fully shared. Evolutionary biologists, the experts on the theory of aging, have strong reasons to suppose that human life span cannot be altered in any quick and easy way. But they have been confounded by experiments with small laboratory animals, like roundworms, fruit flies and mice. In all these species, the change of single genes has brought noticeable increases in life span."


The AGE-Breaker TRC4186 From Torrent Pharmaceuticals

Back in late 2006, a lifetime ago in Internet Time, I briefly mentioned the efforts of Torrent Pharmaceuticals. They are one of the few groups doing any sort of serious work on AGE-breakers, compounds aimed at breaking down the advanced glycation endproducts (AGEs) that build up with age and cause all sorts of havoc in our biochemistry.

One of the ways in which normal metabolic processes degrade important components in your body (such as kidneys, heart, skin and blood vessels) is through the generation of advanced glycation endproducts (AGEs). Your body needs certain proteins in order to work properly; the creation of AGEs involves taking two or more of these proteins and sticking them together with chemical gunk, preventing them from doing their jobs. This is known as crosslinking; day in and day out, it is taking place in your body. Some AGEs are short-lived but common, growing or declining in population in response to your diet and metabolic peculiarities. Others are very long-lived or impossible for the body to break down; they build up over the years, and eventually there's enough of this gunk to seriously damage you.

Problems caused - or not helped - by AGE buildup include kidney disease, and the many variations of blood pressure and heart conditions caused by a lack of elasticity in the tissues of heart and blood vessels. Diabetics in particular suffer due to more rapid accumulation of AGEs based on their metabolic biochemistry (e.g. high blood sugar, inflammation, free radicals).

AGEs may cause harm by hitting a receptor for AGEs (or RAGE) on cell surfaces. This might be thought of as hammering on a keyboard designed for more subtle inputs; cells constantly receiving input at their RAGE receptor don't behave well - and enough cells behaving badly will cause your organs to degrade, damage themselves, and fail.

In accordance with a SENS-like view of how to move forward to defeat the processes of aging, the best approach to dealing with AGEs is to remove them before they build up to damaging levels. Researchers could search for some form of biochemical, drug, or therapy to safely break down AGEs. Fortunately, we live in an era of rapidly advancing biotechnology in which exactly this sort of this task is becoming ever easier and less costly. Unfortunately, not all that many people are working on it at present.

Torrent Pharmaceuticals researchers recently published an update on their work in developing the AGE-breaker compound TRC4186 for commercial use:

TRC4186 is an AGE-breaker that has been evaluated in vitro and in vivo and shown to reduce AGE burden. The aim of this study was to determine the effect of TRC4186 on diabetic cardiomyopathy and nephropathy in [an] animal model of diabetes with progressive cardiac and renal dysfunction.


TRC4186, an AGE-breaker, clearly preserved cardiac function and reduced the severity of renal dysfunction in [an] animal model with persistent severe hyperglycemia leading to diabetic heart failure and renal failure.

As an aside, most commercial AGE-breaker research focuses on diabetes because regulatory bodies such as the FDA do not recognize aging or "normal" AGE accumulation as diseases, and won't approve any medical application of therapies to that end. Thus researchers are forced into channeling research towards officially approved and defined diseases that happen to include some of the same issues in their pathology. Diabetes is the best option for commercial application of AGE-breakers under these imposed limits because of its biochemistry and the fact that it is widespread in this age of too much food and not enough exercise.

Without meaning to denigrate the hard work of the researchers here, TRC4186 isn't all that exciting based on these results. In fact, this looks very much like a repeat of ALT-711 or alagebrium, an early AGE-breaker compound - predating modern designer drug methodologies enabled by new biotechnology - that performed well in rats but terribly in humans. As it turns out, the difference in rat versus human life span leads to very different types of AGEs being important. The lesson learned there is that animal studies of AGE-breakers are in no way a convincing demonstration of their utility, as is unfortunately sometimes the case in new medical technology.

ResearchBlogging.orgJoshi, D., Gupta, R., Dubey, A., Shiwalkar, A., Pathak, P., Gupta, R., Chauthaiwale, V., & Dutt, C. (2009). TRC4186, a Novel AGE-breaker, Improves Diabetic Cardiomyopathy and Nephropathy in Ob-ZSF1 Model of Type 2 Diabetes Journal of Cardiovascular Pharmacology, 54 (1), 72-81 DOI: 10.1097/FJC.0b013e3181ac3a34

Aubrey de Grey's Seminar at Science World 2009

Here's video of a recent presentation by biomedical gerontologist and longevity science advocate Aubrey de Grey: "Dr Aubrey de Grey, author of the book 'Ending Ageing', explains in a clear, concise way in which it may be possible to add years onto the average life expectancy of a human being. Biological ageing is a progressive, degenerative process of decay. As ageing damage accumulates in our functional cellular and molecular structures, the healthy order laid down in our youth slowly falls apart. This damage occurs, as a result, of a series of unintended biochemical side effects of normal metabolism. As more and more of our cellular and molecular structures suffer this damage, functionality is lost, and health, resilience and vitality are slowly taken away from us, leading to increasing age-related pathology. Thus, metabolism causes ongoing ageing damage; this eventually accumulates to reach a critical mass at which it causes age-related frailty, disability, disease, and ultimately death. Aubrey looks at what approaches are already being taken e.g. in the areas of Geriatrics and Gerontology and introduces a third theoretical approach: SENS, which targets the damage of ageing itself, bringing it down to levels below the threshold at which it causes problems."


For Those Who Wanted to Know More About Genescient

I notice that Genescient's newly relaunched website is up and running, and provides much more information as to what the company is up to: "Our focus is to extend healthy human lifespan by using advanced genomics to develop therapeutic substances that attack the diseases of aging. We are the first company founded to exploit artificial selection of animal models for longevity. Our extremely long-lived animal models (Drosophila melanogaster) have been developed over 700 generations. They are an ideal system for the study of aging and age-related disease because Drosophila metabolic genetic pathways that are highly conserved in humans. Our sophisticated analysis cross-links gene function in Drosophila with their human orthologs, thus revealing the targets for therapeutic substance development. To date we have discovered over 100 of these genomic targets, all related to the primary diseases of aging. This large library of targets, enables Genescient to effectively select and test therapeutic drug candidates. To date, Genescient's 'proof-of-concept' testing program has yielded a number of very promising therapeutic substances."


On Photoaging of Skin

The latest issue of the Journal of Investigative Dematology Symposium Proceedings includes a set of papers theorizing on the mechanisms by which exposure to sunlight accelerates the characteristic ways in which skin changes with age. In many ways its a good illustration of just how far there is to go in pulling together present knowledge of aging biochemistry into theories that are both unifying and specific: the researchers here argue on mechanisms from a number of quite different and distinct viewpoints.

Some of the papers are presently free to read, so take a look while that lasts.

Telomere-Mediated Effects on Melanogenesis and Skin Aging

UV-induced melanogenesis (tanning) and "premature aging" or photoaging result in large part from DNA damage. This article reviews data tying both phenomena to telomere-based DNA damage signaling and develops a conceptual framework in which both responses may be understood as cancer-avoidance protective mechanisms.

Role of Mitochondria in Photoaging of Human Skin: The Defective Powerhouse Model

The exact pathogenesis of photoaging of the skin is not yet known. Earlier, a number of molecular pathways explaining one or more characteristics of photoaged skin have been described, but a unifying mechanistic concept is still missing. Here we propose the "Defective Powerhouse Model of Premature Skin Aging", which reconciles most of the earlier conducted research as one concept. In this model, the persistence of UV radiation-induced mtDNA deletions or the infrared radiation-induced disturbance of the electron flow of the mitochondrial electron transport chain leads to inadequate energy production in dermal fibroblasts. As a consequence of this defective powerhouse, retrograde mitochondrial signaling pathways are triggered that then they transduce functional and structural alterations in the skin.

Matrix-Degrading Metalloproteinases in Photoaging

UV radiation from the sun impacts skin health adversely through complex, multiple molecular pathways. Premature skin aging (photoaging) is among the most widely appreciated harmful effects of chronic exposure to solar UV radiation. Extensive damage to the dermal connective tissue is a hallmark of photoaged skin. Disruption of the normal architecture of skin connective tissue impairs skin function and causes it to look aged. UV irradiation induces expression of certain members of the matrix metalloproteinase (MMP) family, which degrade collagen and other extracellular matrix proteins that comprise the dermal connective tissue. Although the critical role of MMPs in photoaging is undeniable, important questions remain.

Researchers are largely on the same page when it comes to how aged skin is different from young skin - questions revolve around the processes that lead to that point. As for aging research in general, you can see camps in any sub-field - such as skin aging here - emerge and center around known areas of interest such as mitochondrial damage, telomere shorting, or nuclear DNA damage.

As in other parts of aging research, no great resolution has been reached as to how much each of these processes contribute to overall degeneration, and which processes might be cause or effect of other processes. All sides have indirect evidence to point to in support of their position, so this might continue for another decade before an evidence-backed consensus emerges.

ResearchBlogging.orgKrutmann, J., & Schroeder, P. (2009). Role of Mitochondria in Photoaging of Human Skin: The Defective Powerhouse Model Journal of Investigative Dermatology Symposium Proceedings, 14 (1), 44-49 DOI: 10.1038/jidsymp.2009.1

Investigating Genetics in the Oldest Healthy People

This open access paper contains an interesting discussion of genetic investigations in the oldest of people who manage to avoid age-related disease and stay comparatively healthy: "Individuals who live to 85 and beyond without developing major age-related diseases may achieve this, in part, by lacking disease susceptibility factors, or by possessing resistance factors that enhance their ability to avoid disease and prolong lifespan. ... Besides genes that have been shown to affect lifespan in animal models, a limited number of genetic variants have been reported to be associated with long life in humans. These studies mainly evaluated genetic variation linked to extreme human life spans (e.g. centenarians) without focusing specifically on health. ... Controversy exists regarding the contribution of these and other gene variants to aging and longevity, because replication studies in different populations, as for replication studies in complex diseases, more often than not fail to confirm the initially reported associations. ... Healthy aging is a complex phenotype likely to be affected by both genetic and environmental factors. We sequenced 24 candidate healthy aging genes in DNA samples from 47 healthy individuals aged eighty-five years or older (the 'oldest-old'), to characterize genetic variation that is present in this exceptional group. These healthy seniors were never diagnosed with cancer, cardiovascular disease, pulmonary disease, diabetes, or Alzheimer disease."


Reminder: Aging and Healthy Lifespan Conference

A reminder that the Aging and Healthy Lifespan Conference will be held on September 23rd - next month - at Harvard Medical School. "Over the next 20 years, the population of Americans over age 65 is expected to double, and health care spending is projected to increase by 25%. With an aging society, it is crucial to understand the challenges and address the opportunities to target diseases of aging, such as cancer and type 2 diabetes, to allow people to live longer, healthier lives. ... Hear leading experts discuss emerging research into scientific and medical advances in aging, as well as lifestyle and demographic trends. This first-ever conference will feature two speaker tracks. One track will focus on new research and insights in the science of aging including updates on the exciting science behind sirtuins and resveratrol. The second track will feature emerging social trends in lifestyles, behaviors and activities of the aging population." Note that longevity science advocate Aubrey de Grey and a number of speakers from the Calorie Restriction Society will be there, alongside researchers whose names I'm sure you'll recognize.


"A Horrifying Idea"

Here is a little reminder that we advocates for longevity have a way to go yet on overcoming the first knee-jerk reaction people have against living longer. Scroll down in a little in this BBC World Service page of audio players for an interview with biomedical gerontologist Aubrey de Grey. The lead-in:

People are certainly living longer, but would it be possible to extend life indefinitely?

Aubrey de Grey is the chair of the SENS Foundation, which studies regenerative medicine solutions to the disabilities and diseases of ageing. He believes that within just a few decades science could put a stop to ageing altogether. The World Today's Pascale Harter finds that a horrifying idea, but Aubrey de Grey says we just haven't grasped it yet.

It's a funny world we live in: that "putting a stop to aging" is instinctively opposed by so many on first hearing of it; that this opposition is the dominant reaction rather than "ah, so I wouldn't have to suffer all those horrible degenerations and a miserable death. Good."

We humans are a species of technology, achievement, and change - when we put our minds to it. The biggest hurdle on the way to extending our healthy life spans is that very, very few of us in the grand scheme of things have decided that longer life is a good idea and pitched in to help make it happen.

Cancer Mortality Rates Have Trended Down

Cancer mortality rates have declined for decades now, a trend that we should expect to see continue and accelerate given the technology demonstrations emerging from the laboratories: "Our efforts against cancer, including prevention, early detection and better treatment, have resulted in profound gains, but these gains are often unappreciated by the public due to the way the data are usually reported ... Cancer mortality rates are usually reported as composite age-adjusted rates. These rates have been declining modestly since the 1990's. However, these statistics heavily emphasize the experience of the oldest Americans for whom mortality rates are the highest. As a result, trends emerging in younger Americans can be concealed. As an alternative to age-adjustment, Kort examined cancer mortality rates stratified by age and found that for individuals born since 1925, every age group has experienced a decline in cancer mortality. The youngest age groups have experienced the steepest decline at 25.9 percent per decade, but even the oldest groups have experienced a 6.8 percent per decade decline."


Can Regenerative Medicine Defeat Aging?

Here biomedical gerontologist Aubrey de Grey defines "regenerative medicine" somewhat more broadly than just stem cell therapies and enhanced healing: "The human body is, ultimately, a machine - an astronomically complex machine, of whose workings we remain pitifully ignorant - but still a machine. Like any machine, it accumulates 'damage' as a side-effect of its normal operation: molecular and cellular changes that occur throughout life are initially harmless, but eventually (when too abundant) increasingly impede the normal operation of the machine and eventually cause it to fail altogether. ... The relevance of nearly all biogerontology research to combating aging is restricted to the potential for slowing down the accumulation of molecular and cellular damage that eventually leads to age-related ill-health. Meanwhile, regenerative medicine has been progressing rapidly and is nearing clinical applicability to a wide range of specific conditions. My view is that we are approaching the point where regenerative medicine can be used against aging. This would entail not retarding but actually reversing the accumulation of damage. If successful, this would obviously be a far more valuable technology than mere slowing of aging. However, in order to be successful it must be comprehensive, and some aspects of aging may seem impossible to address in this way. In fact, however, it seems that all types of molecular and cellular damage which contribute to age-related ill-health are realistic targets of regenerative interventions."


This Should Be Interesting

Per a press release I stumbled over today, Aubrey de Grey and S. Jay Olshansky will be debating longevity science at an investment-focused actuarial conference at the end of next month:

Longevity estimates continue to exert a major influence on the value of life settlement investments. Over the past few years, estimates have changed and, in some cases, dramatically affected the value of portfolios. The future of human longevity and the possibility of radical lifespan extension have caused some uncertainty among this investing community. The Medical Life Expectancy Debate will present both sides of the fundamental question: Is radical human lifespan extension within our grasp?

Dr. de Grey, arguing for the motion, states: "Radical postponement of age-related ill-health is a feasible medical goal." De Grey argues that there is a 50% chance of life extension therapies arriving in 25-30 years. If that happens, lifespans could theoretically be extended almost indefinitely and it’s possible that the first person to live for a thousand years is actually alive today.

Dr. S. Jay Olshansky, on the other hand, makes the case that radical life extension is not going to happen - if it ever happens - in time to influence any of the investment decisions made by those involved with life settlements or insurance linked securities. Olshansky continues, "Nothing in gerontology comes close to fulfilling the promise of dramatically extended human lifespans, but it may soon be possible to slow aging enough to influence ILS in the near-term."

Insofar as anyone gets to be appointed spokesperson, de Grey and Olshansky might be considered spokespeople for the two opposing viewpoints on research strategy in the pro-longevity gerontology community today. On the one hand we have the Strategies for Engineered Negligible Senescence that focus on repair of damage and circumventing incomplete understanding of our biochemistry, with the goal of reversing aging and rejuvenating the old as soon as possible. On the other hand, we have the Longevity Dividend and metabolic engineering, efforts with a focus on establishing complete understanding of our biochemistry and using that understanding to slow down the ongoing progression of aging.

Note that there are ever fewer voices from the scientific community arguing that we should not or cannot significantly intervene in the aging process. The consensus is that we can, and the important debates are all now over methodology and timelines.

By far the dominant view in the aging research community at present is that metabolic engineering to slow aging is the only viable way forward to longer, healthier lives. This is unfortunate, because metabolic engineering doesn't seem likely to produce results any faster than SENS-like strategies at a given level of research investment, and it won't produce end results that are of any great benefit to people who are already old. Slowing aging by slowing down ongoing damage isn't worth much to someone who is already damaged and old. (Those people who are already old and damaged will include most of you reading this now given the expected timeline of development).

That said, it is promising to see both sides presenting their views to a wealthy and interested community. I've posted on the topic of actuaries and the life insurance industry in the past; vast sums of money rests upon projections of life expectancy, and the uncertainty in those projections stemming from the biotechnology revolution is causing ever more attention to be directed towards longevity science in those quarters. Hopefully some of those folk will take time away from thinking about their portfolios to ponder their personal futures and how they can influence those futures by supporting longevity research.

Calorie Restriction, Intermittent Fasting, and Cancer Risk

FuturePundit looks at one of a number of studies showing calorie restriction to reduce the risk of cancer: "Previous studies have shown that intermittent calorie restriction provided greater protection from mammary tumor development than did the same overall degree of restriction, which was implemented in a chronic fashion. The researchers compared changes of a growth factor (IGF-1) in relationship to these two calorie restriction methods - chronic and intermittent - and tumor development beginning in 10-week old female mice at risk to develop mammary tumors. Their hope was to explain why intermittent restriction is more effective. The overall degree of restriction was 25 percent reduction compared to control mice. Mammary tumor incidence was 71 percent in the control mice who ate the amount of food they wanted, 35 percent among those who were chronically restricted and only nine percent in those who intermittently restricted calories." Which is further evidence for those who suspect that intermittent fasting operates through different biochemical mechanisms to calorie restriction, despite a similar outcome in terms of extended health and longevity.


Veterinary Use of Stem Cell Therapies

The widespread veterinary use of stem cell therapies in past years well demonstrates that there is no good reason for regulatory barriers blocking human application of these technologies: "Vet-Stem, a Poway, Calif.-based company, is developing the stem cell therapy and began treating horses in 2003. It derives stem cells from fat samples taken from dogs and horses across the country. The procedure has been used mainly to treat osteoarthritis, which involves loss of cartilage in the joints, but Vet-Stem is researching treatments for other diseases. Vet-Stem claims the therapy enables animals to replace cartilage and other tissue. Since 2003, the privately held company has treated 3,500 horses and 1,500 dogs and plans to begin treating cats later this year. More than 1,500 vets are licensed to use the procedure. ... Really, all we're doing is harnessing the existing repair machinery in the body, concentrating it, and putting it right where an injury occurs, where healing is needed, to heal naturally. ... One peer-reviewed [study] sponsored in part by Vet-Stem, found that tendinitis in horses was improved by injection of the adult stem cells. Two other studies published in Veterinary Therapeutics found that dogs with osteoarthritis showed improvements in lameness after stem cell injections. Those studies also were sponsored by Vet-Stem and conducted by Vet-Stem researchers and other veterinarians."


Laser Ablation Research Fundraising Deadline is Monday, August 17th

As you no doubt know by now, the Immortality Institute is raising $8000 in public donations that will then be matched up to $16,000, that money going towards the validation of laser ablation of lipofuscin as a longevity therapy. From the project and donation page:

This research proposes to further study the use of laser pulses to destroy lipofuscin. The technical term for this approach is Selective Photothermolysis. LEDs, lasers, and infrared light have already found their way into many clinical and cosmetic applications. This research will investigate the use of laser pulses to improve human health at a much more fundamental level.

Mr. Schooler has conducted preliminary qualitative research using laser pulses to destroy lipofuscin in nematodes (round worms). VIDEO HERE. This investigation was the subject of a presentation at the UABBA conference at UCLA in 2008. The current proposed research will use various pulsed laser treatments to investigate the effects on worm lifespan. Human cell culture models will also be used to investigate the dynamics of lipofuscin destruction microscopically in actual human cells.

Lipofucsin is an aggregate of many different biochemical byproducts that builds up in your longest-lived cells, leading to dysfunction and disease. Lipofuscin levels are a very straightforward difference between old and young people, and removing it at regular intervals should have a noticeable impact on age-related degeneration. This is in fact an aspect of one of the seven avenues of Strategies for Engineered Negligible Senescence (SENS) research - removing damaging aggregates from the body.

I will say that the Immortality Institute folk are doing a fine job of grassroots fundraising in what is a terrible economic climate for any sort of non-profit activity, but they have a way to go yet for their target and the deadline for the fundraising initiative is Monday 17th. So if any of you reading this have stopped to think in recent years that research isn't moving fast enough for your liking, then why not jump in and donate a few dollars? Things only happen when you make them happen.

The present donation matching offered by generous folk in the Institute forums amounts to a sixfold multiplication of your money: donate $30 and $180 will go to support this research project. As I explained the last time I mentioned this initiative, this is an excellent example of a high-impact, low-cost, short-term project that can open many doors if successful.

Validating the use of lasers as an approach to remove the buildup of lipofuscin in our cells and thereby help long-term health and longevity won't cost much - a few tens of thousands of dollars. So give a little of your spare change to help move this research to its conclusion: it's a good bet, and supporting this per-project grassroots methodology of funding biotechnology research is also a good bet. If this one is well funded, we'll be seeing more diverse SENS research projects put forward and funded by the community in the future.

Theorizing on Sirt3 and Longevity Mechanisms

This research group proposes that Sirt3 acts on longevity through increasing antioxidants - we should all be appropriately skeptical, given the very mixed evidence for links between cellular antioxidants and longevity. That said, Sirt3 is located in the mitochondria, and the demonstrations of extended life spans through increased antioxidants have involved targeting those antioxidants to the mitochondria. "Sirtuin 3 (SIRT3) is a member of the sirtuin family of proteins that promote longevity in many organisms. Increased expression of SIRT3 has been linked to an extended life span in humans. ... Of the 7 SIRT analogues, SIRT3 is the only member whose increased expression has been linked to the longevity of humans. Polymorphism in the SIRT3 gene promoter, which leads to gene activation, has been found to be associated with an extended life span of man. The molecular basis of SIRT3-dependent longevity is, however, not known. ... In primary cultures of cardiomyocytes, Sirt3 blocked cardiac hypertrophy by activating the forkhead box O3a–dependent (Foxo3a-dependent), antioxidant–encoding genes manganese superoxide dismutase (MnSOD) and catalase (Cat), thereby decreasing cellular levels of ROS. ... These results demonstrate that SIRT3 [protects] hearts by suppressing cellular levels of ROS."


Creating Blood Cells To Order

Creating patient specific blood cells will enable many, many applications - especially in an era of immune therapies. Even the simple ability to greatly multiply the number of white blood cells in a patient's body for a short while can be profoundly beneficial. Here is an update on progress towards engineered blood cells made to order: "In an advance that could help transform embryonic stem cells into a multipurpose medical tool, [scientists] have transformed these versatile cells into progenitors of white blood cells and into six types of mature white blood and immune cells. While clinical use is some years away, the new technique could produce cells with enormous potential for studying the development and treatment of disease. The technique works equally well with stem cells grown from an embryo and with adult pluripotent stem cells, which are derived from adult cells that have been converted until they resemble embryonic stem cells. If the adult cells came from people with certain bone marrow diseases, the new technique could produce blood cells with specific defects. It could also be used to grow specific varieties of immune cells that could target specific infections or tumors."


The Cancer Stem Cell Theory Continues to Look Promising

I can't say that I'm too concerned about the prospects of cancer in my future. Short of being very unlucky and suffering a rare early life occurrence of cancer, I, and anyone in their middle age in a developed nation, will mostly likely suffer cancer only after medical technology has advanced to the point at which cancer is a non-issue. Dealing with it will cost time and money, but you won't die and you won't suffer any of the trauma associated with today's destructive cancer treatments.

A number of trends in the field of cancer research have been moving rapidly in recent years, backed by large amounts of funding, and supported by large, self-sustaining scientific communities. There is a great deal of momentum inherent in the cancer research institutions of the world and the surrounding industries of biotechnology. Nothing is going to slow down or grind to a halt any time soon, and progress in fundamental research is if anything speeding up as the tools improve in lockstep with computing power.

Firstly, new biotechnology is making possible the effective detection and destruction of cancer cells. These cells are different from normal cells in ways that can be exploited to (a) identify cancers at the very earliest stages when even present day treatments can destroy them safely, (b) build new treatments that target and destroy even advanced cancers, harming only cancer cells and causing no side-effects or damage to healthy cells in the body.

A second, related line of research centers on cancer stem cells:

The promise - the hoped for possibility - of cancer stem cells is that they represent a small, manageable, less complex range of biochemical targets to prevent and destroy cancer. The biotechnology of this year and next can flip genetic switches and safely destroy cells with specific markers - if we just know where to look, what to destroy, what to change.

The promise of cancer stem cells is that cancer has a simple, easily severed root. This may or may not be the case, but you can be sure that this path will be well explored over the next decade.

As noted, a vigorous scientific debate is presently underway. Are cancer stem cells damaged versions of normal stem cells, and do they exist in all cancers? Or are there characteristic ways in which normal cells become reprogrammed into cancer stem cells? After all, induced pluripotent stem cells show that normal cells can be altered in just a few ways to give them the characteristics of embryonic stem cells - such as unchecked growth. Or is it the case that cancers, mutating rapidly, will generate a huge variety of stem-like cells to support their growth, and thus there are few if any commonalities to target?

All of these points of view presently have some experimental results to back them up. New results continue to be published at a pace that suggests it won't be too many more years before the contradictions are reconciled and the important question answered: are cancer stem cells a short cut to killing most or all cancers? At present it looks plausible that the answer is yes.

Here's a recent example of research that supports the damaged stem cell viewpoint:

n the new study, led by Berman's postdoctoral research fellow Xiaobing He, Ph.D., the researchers reasoned that if these stem-like cancer cells behave like healthy stem cells, they might be physically located in the same compartments in tissue where stem cells normally reside. Using a surface protein marker previously identified for healthy bladder stem cells, the Hopkins team searched for cells with the same marker in sections from 55 human bladder tumors. They found that cancer cells displaying the marker were localized in an area at the intersection of two layers of cells known as epithelium and stroma, the place where bladder stem cells are typically located.

Using cancer cell lines grown from other bladder cancer patients, the researchers separated cells displaying the stem cell marker from those without it and injected these two populations into different sets of mice. Mice injected with the cancer cells displaying the marker always grew tumors, but those injected with the other cancer cells rarely did, suggesting that the stem-like cancer cells have an ability to create new tissue much like healthy stem cells do.

I think it's fair to say that if the cancer stem cells in bladder cancer resulted from errant reprogramming of normal cells, you would not expect to find them localized where normal stem cells usually exist.

What Cell Reprogramming Teaches Us About Cancer

As researchers continue to discover and manipulate the mechanisms of cell programming, the new knowledge generated will impact many other fields of medicine: "research links cancer development with difficulties in the new technology of reprogramming normal cells into becoming like embryonic stem cells ... Nearly all cancers have a disabled p53 gene. The gene causes cells that have experienced major genetic damage, which puts them at high risk of turning malignant, to self-destruct. While several mutated genes are implicated in cancer, p53 appears to be the most important one. ... When the p53 gene is removed, normal cells can be reprogrammed into stem cells with a tenfold greater success rate ... If the link is confirmed by other researchers, it would undermine a popular hypothesis that cancers arise from 'cancer stem cells,' caused by genetic changes in stem cells. [Instead] cancer could begin when normal cells spontaneously reprogram themselves, for reasons yet unknown, beginning the process that results in a cancerous tumor. ... A better understanding of how to cause reprogramming could provide clues about how this might arise spontaneously. And that knowledge could be useful in developing cancer-fighting therapies."


Cancer Stem Cells in Brain Cancer

More interesting cancer stem cell research: "researchers report that the STAT3 gene regulates cancer stem cells in brain cancer. Cancer stem cells have many characteristics of stem cells and are thought to be the cells that drive tumor formation. The researchers report that STAT3 could become a target for cancer therapy, specifically in Glioblastoma multiforme (GBM), a type of malignant and aggressive brain tumor. ... STAT3 has been shown to be activated in a number of human tumors. This study is one of the first to show, however, that STAT3 regulates cancer stem cells. It is one of the few genes linked to the propagation of cancer stem cells, and it appears to regulate processes involved in the six hallmarks of cancer: growth, metastasis, angiogenesis, evasion of apoptosis, tissue invasion, and cell immortalization. ... Current cancer therapies that prolong life do not specifically target cancer stem cells, and these cells are often resistant to traditional radiation and chemotherapies. ... When STAT3 is inhibited, cancer stem cells in glioblastomas lose their stem-cell characteristics permanently, suggesting that STAT3 regulates growth and self-renewal of stem cells within glioblastomas. Strikingly, a single, acute treatment with STAT3 inhibitors was effective, implying that a STAT3 inhibitor could stop tumor formation."


Wired on the Longevity Dividend

I see that Wired is running a piece espousing the Longevity Dividend. The Longevity Dividend is an argument developed by a group of gerontologists and aimed at regulators and politically-influenced funding groups. It deliberately steers clear of talking about extending life span, instead presenting increased funding for applied aging research as a form of investment that will greatly reduce later government medical program expenditures through reducing incidence of age-related disease. In that sense it is a form of compressed morbidity viewpoint, the theory that the period of life spent in age-related frailty and suffering from age-related disease can be compressed down without extending life span. This runs contrary to aging-as-damage theories, which instead state that any intervention that reduces the level of accumulated damage will tend to extend overall life span in addition to its other beneficial effects.

As to my personal view, I'll say that there are many strategies by which one can advance a cause - here, the cause of longevity science. Advocacy strategies that water down or omit core goals and facts in order to achieve wider circulation will do little to change the marketplace of ideas, however, and it is change in the marketplace of ideas that drives progress. The best progress in advocacy is made by planting your flag as far out as is supported by the evidence, and then defending that point against all naysayers.

But of course only the boldest of folk are willing to do that. Large institutions, such as government funding sources and the associated research communities, are ruthless in punishing members who publicly step one iota behind the limits of tradition and convention - hence the softly softly approach by those who have the most to lose.

Back to the topic at hand, here's the article in Wired:

As politicians try to reform a health care system that could swallow one-fifth of the nation’s economic output by 2020, they should consider making a small bet with a potentially huge payoff: research that could slow the process of aging.

"There will never be enough money for the federal government to pay for the demands of health care, because of chronic age-related diseases," said Doug Wallace, a cell biologist at the University of California, Irvine.

Wallace specializes in mitochondria - cellular power plants that float outside the cell nucleus, turn glucose into usable energy, and wear down over time. He thinks their malfunction underlies nearly every disease whose risks spike after middle age, from cancer to heart disease to dementia.


In papers published in The Scientist and British Medical Journal, Olshanksy and International Longevity Center president Robert Butler wrote that drugs that delay aging’s onset by seven years are now a realistic possibility.

They’re currently in the process of calculating this longevity dividend’s economic benefits. Even if the figures aren’t finalized, however, they’re likely to be massive. For Alzheimer’s disease alone, they estimate that the cost of care will rise to $1 trillion by 2050. The Robert Wood Johnson foundation estimates two-thirds of rising health costs come from chronic diseases.

“We need a method of molecular pre-emption. If we’re going to be able to afford health care, that’s what we’ve got to do. That’s going to provide the maximum cost savings, not managing symptoms or curative treatment,” said former National Institutes of Health chief Elias Zerhouni at a symposium held last Friday by the Jackson Laboratory.

I'll point you to a good quote from a little while back:

I say if this were a privatized system, we would all say "gee it’s wonderful. All these people want more health care, this industry is thriving". Let me put one other analogy. Suppose we made cars a government entitlement. Instead of cheering when auto production went up, we’d say, "Oh my God, we can’t afford this!". How you finance it may greatly affect the psychology and actually the freedom of the economy to take advantage of these new opportunities.

Centralized government control destroys everything it touches; it's just a matter of time for US medical institutions. It will be the tragedy of the commons writ larger than ever, a system in which every local, personal incentive is aligned against progress. So we will have little progress - and consequently much suffering - until some revolution sweeps this all away.

A Case For Spurring More Neurogenesis

In the near future it will be possible to increase the rate at which new neurons and neural connections are created in the brain. This looks promising as a way to tackle some aspects of age-related decline: "Newborn neurons are continuously produced in the hippocampus, which may be involved in several cognitive functions, including learning and memory, throughout life. However, both hippocampus-dependent cognitive functions and the level of adult neurogenesis are gradually attenuated as aging progresses. Few studies have explored the relationship between adult neurogenesis and cognitive functions, especially in primates. In this study, we evaluated learning performance and hippocampal neurogenesis utilizing young and aged cynomolgus monkeys. Significant attenuations in learning performance and adult neurogenesis were detected in aged monkeys. Interestingly, there was a positive correlation between learning performance and the level of neurogenesis. Our findings suggest that cognitive functions and adult neurogenesis may have some interdependent relationships during aging."


Reprogramming an Exhausted Immune System

The immune system declines and malfunctions with age, but researchers are making strides towards methods of reprogramming that might restore an age-damaged immune system to better operation: researchers have "identified a protein that could serve as a target for reprogramming immune system cells exhausted by exposure to chronic viral infection into more effective "soldiers" against certain viruses like HIV, hepatitis C, and hepatitis B, as well as some cancers, such as melanoma. ... the protein Blimp-1 (B-lymphocyte-induced maturation protein 1) represses the normal differentiation of CD8 T cells into memory T cells, which recognize disease-causing agents from previous infections and enable the body to mount faster, stronger immune responses. The team also reports that Blimp-1 causes exhausted CD8 T cells to express inhibitory receptors, which prevent recognition of specific antigens, further weakening immune response. The researchers describe how complete deletion of Blimp-1, which is overexpressed in CD8 T cells during chronic viral infection, reversed these aspects of T cell exhaustion." Note that one important cause of immune system aging is chronic infection by cytomegalovirus - this work probably has relevance to aging.


Point Mutations in Mitochondrial DNA and Aging

Hopefully by now most folk here know that mitochondria are the power plants of our cells, toiling in their thousands inside each cell to turn food into ATP, a chemical used as fuel by other cellular processes. Mitochondria contain their own DNA, separate from the DNA in the cell nucleus, a legacy of their symbiotic nature. If some crucial portions of that DNA are damaged, then a mitochondrion will become dysfunctional - and a Rube Goldberg process unfolds from this point, causing age-related degeneration as damage to mitochondrial DNA spirals outwards into increasing forms of disarray and damage in and around your cells.

Unfortunately, mitochondrial DNA is comparatively unprotected, and sits right next to the mitochondrial food-processing machinery that produces all sorts of reactive, damage-inducing molecules as a matter of course. In theory a cell's repair and recycling mechanisms should destroy damaged mitochondria before things get out of hand, but in practice it doesn't work that way enough of the time. Hence damage accumulates over the years, and we witness the results of that damage as some fraction of the degenerations of aging.

What I've outlined in the paragraphs above is the mitochondrial free radical theory of aging. You can read more of the details back in the Fight Aging! archives.

Damage to DNA is also known as mutation - any change in the molecular structure that throws a spanner in the works. But there are numerous different forms of mutational damage, ranging from tiny point mutations to terrible double strand breaks or linear deletions in which whole regions are snipped out of DNA.

A little while back, one group of researchers was arguing against the mitochondrial free radical theory of aging on the basis of mice loaded up with point mutations in their mitochondrial DNA:

The data, which contradict a prominent theory that mitochondrial mutations drive the aging process, show that mice with mitochondrial mutations 500 times higher than normal levels do not show signs of premature aging.

The response to this from other researchers was much along the lines of "well of course it's not point mutations - the real culprit is large deletions in mitochondrial DNA that happen to knock out one of the dozen or so crucial genes used to build the mitochondrial machinery."

I noticed a paper today that muddies the waters further - you'll see a lot of that in any active field of research. The researchers claim that point mutations are in fact sufficient to cause issues, but not in a direct fashion. The affected mitochondrial machinery is the respiratory chain or electron transport chain, a mechanism that cycles various molecules and electrons through a process that generates ATP:

The mtDNA mutator mice have high levels of point mutations and linear deletions of mtDNA causing a progressive respiratory chain dysfunction and a premature aging phenotype. We have now performed molecular analyses to determine the mechanism whereby these mtDNA mutations impair respiratory chain function. We report that mitochondrial protein synthesis is unimpaired in mtDNA mutator mice consistent with the observed minor alterations of steady-state levels of mitochondrial transcripts.

These findings refute recent claims that circular mtDNA molecules with large deletions are driving the premature aging phenotype. We further show that the stability of several respiratory chain complexes is severely impaired despite normal synthesis of the corresponding mtDNA-encoded subunits.

To translate: point mutations don't interfere with the production of proteins needed to build the respiratory chain, but they can make this machinery unstable and inefficient. This can lead to much the same end result as losing a vital gene completely to a more serious mutation, and here it leads to premature aging in mice engineered for point mutations.

That one group of researchers has point-mutation-bearing mice that age normally and another group has point-mutation-bearing mice that age faster indicates that there's more to this story, however. Something is unknown, always the case when solid research appears to be contradictory, and more research is needed to get to the bottom of the mechanisms here. But note that we could sidestep all of these issues with a technology that repairs or replaces mitochondrial DNA globally throughout the body - such as protofection, demonstrated back in 2005. If we replace all mitochondrial DNA with fresh new mitochondrial DNA, then it doesn't matter why or how its prior state was causing issues because we just fixed the problem.

This is as good an example as any to show that we don't need complete understanding of human biochemistry in order to make important inroads into repairing the damage of aging. More understanding helps, but we have enough knowledge now to move ahead with significant and important rejuvenation technologies - were there a large research community and the will and funding to forge ahead. But here, as in so many nascent fields of biotechnology with great potential, we are left lacking. There is no large research community focused on replacing mitochondrial DNA, and to the best of my knowledge only a few small groups are presently working on this sort of technology.

If you wish to understand why this is the case, you might look at the regulatory environment. The FDA will not approve treatments for aging, and - in conjunction with a pharmaceutical industry happy to squash disruptive upstart companies - ensures that commercial development of new medical technology is made so ridiculously expensive that no great interest is attached to minority diseases. Mitochondrial diseases beyond aging don't affect enough people to make it financially viable for a large development industry to form under the present constraints. This is generally true of highly regulated industries: experimentation is discouraged, and anything other than the broadest application is made unprofitable.

In the years ahead, with the costs of biotechnology falling ever faster, we'll have to take matters into our own hands if we want to see any real progress.

ResearchBlogging.orgEdgar, D., Shabalina, I., Camara, Y., Wredenberg, A., Calvaruso, M., Nijtmans, L., Nedergaard, J., Cannon, B., Larsson, N., & Trifunovic, A. (2009). Random Point Mutations with Major Effects on Protein-Coding Genes Are the Driving Force behind Premature Aging in mtDNA Mutator Mice Cell Metabolism, 10 (2), 131-138 DOI: 10.1016/j.cmet.2009.06.010

Aptamers and Liposomes for Cancer Targeting

A snapshot of ongoing work to develop cost-effective tools for building targeted cancer therapies: "Scientists have spent more than a decade trying to direct liposomes to specific cancer cells, with limited success. A common approach involves attaching an antibody to the liposome membrane. Ideally the antibody will bind to a cancer cell receptor so that it can deliver the liposome - and the cancer drug - into the cell. Developing such antibodies is costly and time-consuming, however, and the process of attaching them to liposomes is difficult to control. ... Aptamers are short strands of DNA or RNA; they are highly efficient binders, and are very easy to make, label and manipulate ... [researchers] used an aptamer that binds to nucleolin receptors, which are found in abundance on certain breast cancer cells. The researchers then developed an effective method for attaching the aptamer to a liposome loaded with cisplatin, a drug that effectively kills cancer cells but has troublesome side effects when administered intravenously. Tests in cells grown in the lab yielded promising results. Four days after they exposed the cells to the new drug-delivery system, 59.5 percent of the breast cancer cells had died, while less than 12 percent of breast cancer cells treated with cisplatin alone had died. ... Another advantage of using aptamers as targeting agents is that they are easily disabled. They readily bind to complementary DNA, which prevents them from interacting with cell receptors."


On Calorie Restriction

Here, Chemical & Engineering News looks at the practice of calorie restriction: "lthough Paul McGlothin and Meredith Averill are in their early 60s, the married couple from New York State says that they feel at least 20 years younger. This is no idle claim: Their blood pressures, resting heart rates, and body fat percentages rival those of Olympic athletes. ... So what's their antiaging secret? For the past 16 years, McGlothin and Averill have been eating a carefully controlled, calorie-restricted diet. ... Scientists have known for decades that caloric restriction - reducing calorie intake without malnutrition - slows aging and extends life span in model organisms ranging from yeast to mice. Exactly why and how it confers these benefits in animals, and whether similar effects could be attained in humans, have been a mystery. ... Caloric restriction is about more than just being thin and fit. Something about eating a diet that is low in calories but nutritionally complete causes a dramatic reprogramming of cellular metabolism that can't be replicated by exercise or by eating smaller amounts of high-calorie foods. In laboratory animals such as fruit flies, roundworms, and mice, caloric restriction switches biochemical pathways on or off, resulting in higher insulin sensitivity, decreased inflammation, enhanced cardiovascular functioning, reduced muscle wasting with age, and improved resistance to cellular stress. Not only is normal aging slowed, but calorie-restricted animals are also less likely to develop age-associated diseases such as diabetes and cancer."


Melatonin and SIRT1

Let me open by saying that I rarely talk about supplements except to trash them. This is because (a) there are already plenty of people out there talking about nothing but supplements, and (b) there's no scientific evidence that demonstrates the sort of heavy-duty supplement packages advocated today to produce health and longevity benefits in any way comparable to those attained by exercise and calorie restriction. If you're fat and sedentary and you're feeling virtuous because you're taking expensive dietary supplements, you're most likely going to be disappointed in the trajectory of your future health.

Anyway. Today we're going to talk about melatonin because it looks like it triggers the sirtuin SIRT1 in a similar way to resveratrol, and a number of people are interested in following sirtuin research. You might recall that researchers presently believe SIRT1 to work by affecting heat shock proteins and thereby making cellular repair processes more efficient. This research is itself an outgrowth of calorie restriction studies, and it's worth reminding everyone that resveratrol itself hasn't been shown to produce any health benefit that is as effective as calorie restriction. On that basis, a number of researchers are looking elsewhere for the controlling mechanisms of calorie restriction.

Sirtuins remain interesting, however, given that they are connected to all sorts of triggers and switches inside metabolism that relate to longevity, cancer, energy generation, and so forth. Calorie restriction demonstrates that noteworthy benefits can be achieved through manipulation of these controls - the question is whether there is an even better setting that could be attained through drugs or gene manipulation, a setting that slows down aging further than calorie restriction.

A perhaps more pertinent question is whether that better metabolism can be developed and made commercially available before those of us reading this now get old. That's where I have my doubts, and think we'd all be better off if the research community focused more on SENS-like repair strategies and less on slowing down aging by manipulation of metabolism. Slowing aging is a wash if you're already old by the time the medical technology to achieve that goal arrives. Repairing the damage of aging on the other hand...

In any case, here's the paper that caught my eye today, published in the Journal of Pineal Research. A brief scan of past issues suggests this might as well be called the Journal of Melatonin Studies and Nothing Else. I'm impressed - or possibly appalled, I can't decide which - that we live in an age in which a research community exists that can reliably fill a bi-monthly journal with nothing but studies of melatonin:

Sirtuin 1 is a member of the sirtuin family of protein deacetylases, which have attracted considerable attention as mediators of lifespan extension in several model organisms. Induction of sirtuin 1 expression also attenuates neuronal degeneration and death in animal models of Alzheimer's disease and Huntington's disease.

In this study, an in vitro model of neuronal aging was used to test in several ways whether melatonin acts as a sirtuin 1 inducer and if this effect could be neuroprotective. It is shown that melatonin is able to increase the level of this deacetylase in young primary neurons, as well as in aged neurons. We also observed an increase in the deacetylation of several substrates of sirtuin 1, such as p53, PGC-1alpha, FoxO1, ADAM10 and NFkappaB.

Over the past years, you've probably seen all of those substrate genes mentioned here or in the Longevity Meme News. The biochemistry of metabolism is a tangled mess of a machine, and nothing operates independently. All of these genes and the mechanisms they participate in are legitimate areas of study until someone finally sorts it all out with a verifiable grand unified theory of metabolic mechanisms.

ResearchBlogging.orgTajes, M., Gutierrez-Cuesta, J., Ortuño-Sahagun, D., Camins, A., & Pallàs, M. (2009). Anti-aging properties of melatonin in an in vitro murine senescence model: involvement of the sirtuin 1 pathway Journal of Pineal Research DOI: 10.1111/j.1600-079X.2009.00706.x

The Decline of Your Long-Lived Cells

Not all of the cells in your body replace their populations on a regular basis. Some groups of cells will last almost an entire lifetime, and across that lifetime they will become increasingly damaged and dysfunctional. Here is an overview of that process: "It is now generally accepted that aging and eventual death of multicellular organisms is to a large extent related to macromolecular damage by mitochondrially produced reactive oxygen species, mostly affecting long-lived postmitotic cells, such as neurons and cardiac myocytes. ... The inherent inability of autophagy and other cellular degradation mechanisms to completely remove damaged structures results in the progressive accumulation of garbage, including cytosolic protein aggregates, defective mitochondria and lipofuscin - an intralysosomal indigestible material. ... The slow accumulation of lipofuscin within lysosomes seems to depress autophagy, resulting in reduced mitochondrial turnover. The latter are not only functionally deficient but also produce increased amounts of reactive oxygen species, prompting [the creation of lipofuscin]. Moreover, defective and enlarged mitochondria are [only poorly recycled] and constitute a growing population of badly functioning organelles ... The progress of these changes seems to result in enhanced oxidative stress, decreased ATP production, and collapse of the cellular catabolic machinery, which eventually is incompatible with survival." This is the garbage catastrophe of the cell: garbage builds up, which makes things worse and leads to more garbage. Eventually it kills the cell, and enough of this will kill you too.


The Healthy Life Extension Society

I don't think I've pointed out the Healthy Life Extension Society, or Heales before; it's a group based in Belgium, and so you'll find more French and Dutch content than English material at the Society's website. For the rest of us English-speaking monolinguists, there's always Google Translate: "Each day 100,000 people die due to the effects of old age. Aging is responsible for 90% of deaths in the richest countries and two-thirds of deaths in the world. It doesn't just cause innumerable deaths, it is also the source of horrible suffering - Alzheimer's Disease, muscular atrophy, damage to vision and hearing, osteoporosis, rheumatoid arthritis ... The only way to prevent these illnesses linked to aging is to attack the root cause – that is aging itself. It is time to start working towards solutions to this universal human tragedy. Heales raises awareness of new developments in the area of biogerontolgy (the science of aging). We promote and support anti-aging research." As I noted in the latest Longevity Meme newsletter, Heales is holding a fundraising music festival for LysoSENS research next month.


Bats and Birds: High Metabolic Rates, Great Longevity

It's been shellfish every other day of late, but today we'll cast our eyes on another portion of the study of comparative longevity and differing metabolism between species. Birds and bats are both interesting for what they tell us about how metabolic processes determine species longevity:

Bats and birds live substantially longer on average than non-flying mammals of similar body size. The combination of small body size, high metabolic rates, and long lifespan in bats and birds would not seem to support oxidative theories of ageing that view senescence as the gradual accumulation of damage from metabolic byproducts. However, large-scale comparative analyses and laboratory studies on a few emerging model species have identified multiple mechanisms for resisting oxidative damage to mitochondrial DNA and cellular structures in both bats and birds.


New techniques for determining the age of free-living, wild individuals, and robustly-supported molecular phylogenies, are under development and will improve the efforts of comparative biologists to identify ecological and evolutionary factors promoting long lifespan. In the laboratory, greater development of emerging laboratory models and comparative functional genomic approaches will be needed to identify the molecular pathways of longevity extension in birds and bats.

You can also see this sort of biochemical and life expectancy difference in naked mole rats versus other rodents. In the mole-rat case, unlike bats, older animals have a great deal of oxidative damage, but don't seem to be particularly affected by it. That tells us that there are at least a couple of different ways in which the average mammal's metabolism might be made better with respect to oxidative damage - in the sense of being engineered for longer life.

What is learned from bats and naked mole-rats will no doubt be a quite different set of optimizations to those associated with calorie restriction, insulin metabolism, p53 and telomerase, or any of the other longevity mutations and changes demonstrated in recent years. Hypothetically, one could imagine a mouse breed engineered to possess all of these mutations and engineered changes in parallel - and I suspect it won't be too many more years before a research group undertakes that project in earnest.

Still, will this be relevant to those of us reading this today? I suspect not. Upgrading human metabolism is a 2030s project, and something that will plausibly only slow aging. Not so great for those of us who will be pushing 60, 70, or more by then. The best development programs are those that focus on repair rather than enhancement: fix the damage rather than changing the mechanisms to cause less damage. It is repair that is the path to rejuvenation, or reversing the progression of aging in our cells, tissues, and organs.

Sadly, repair is not the primary focus of the aging research community. Most of the pro-longevity researchers are firmly in favor of metabolic engineering to slow aging, and largely focused on the use of drugs to achieve that goal.

Calorie Restriction Slows Thymic Involution

Your thymus is the source of T-cells, the varied workers of the immune system. As you age, the thymus involutes - degenerates - and production of new T-cells fades away. Calorie restriction (CR) slows this process, which is no doubt one of the ways in which it improves immune response: "Aging of thymus is characterized by reduction in naive T cell output together with progressive replacement of lymphostromal thymic zones with adipocytes. Determining how calorie restriction (CR), a prolongevity metabolic intervention, regulates thymic aging may allow identification of relevant mechanisms to prevent immunosenescence. Using a mouse model of chronic CR, we found that a reduction in age-related thymic adipogenic mechanism is coupled with maintenance of thymic function. The CR increased cellular density in the thymic cortex and medulla and preserved the epithelial signatures." The paper then goes into some detail as to the controlling biochemical mechanisms and gene expression that accompanies these changes.


Cancer Stem Cells and a Mechanism of Evasion

Investigating cancer stem cells may uncover useful targets for new selective cell destruction methods, such as this one: researchers "have identified the first human bladder cancer stem cell and revealed how it works to escape the body's natural defenses. ... [the gene] CD47 works to prevent leukemia cells from being engulfed by macrophages by binding to a molecule on the surface of the macrophage. Blocking this interaction with an antibody specific for CD47 allows the macrophages to swallow the leukemia cells. When [researchers] tried a similar experiment with the bladder cancer stem cells in a test tube, the same thing happened - human macrophages began to destroy the cancer cells. ... Leukemia is totally different from the kind of epithelial cancer we see in the bladder, so it was very exciting to see that these two kinds of cancer stem cells use a similar mechanism to escape the macrophages. ... The researchers are now investigating whether CD47 is expressed at high levels on other cancer stem cells and pondering ways to help circulating macrophages better infiltrate solid tumors - always with an eye towards therapy."


Tooth Regeneration is Coming Along Nicely

Amongst the varied practical applications of tissue engineering presently under development, growing replacement teeth has consistantly been near the front of the pack. Given the lower levels of risk involved in working on less vital structures such as teeth and hair, it wouldn't be surprising to see these medical applications of stem cells and tissue engineering brought to widespread clinical use in advance of heart and nerve regeneration.

In any case, here is another step forward towards those shiny new teeth you've been waiting for, grown from your own stem cells:

Fully functioning teeth have been grown from stem cells planted in the mouths of mice, scientists said today.

If you head over to PNAS, you'll find that the paper is open access and the full PDF is available:

The ultimate goal of regenerative therapy is to develop fully functioning bioengineered organs which work in cooperation with surrounding tissues to replace organs that were lost or damaged as a result of disease, injury, or aging. Here, we report a successful fully functioning tooth replacement in an adult mouse achieved through the transplantation of bioengineered tooth germ into the alveolar bone in the lost tooth region. We propose this technology as a model for future organ replacement therapies.

The bioengineered tooth, which was erupted and occluded, had the correct tooth structure, hardness of mineralized tissues for mastication, and response to noxious stimulations such as mechanical stress and pain in cooperation with other oral and maxillofacial tissues.

Much of this paper is concerned with establishing that, yes, this tooth is functionally sound and fully integrated with surrounding bone, tissue, and nerves - which is a big deal. It's all too easy to envisage techniques of tissue engineering that fail for one reason or another to generate the correct form of large-scale tissue growth. Japanese research groups have been turning out a number of interesting and important advances in past years, and here they've managed it again.

Calorie Restriction Enhances Immune Response

Another example of calorie restriction improving immune system performance, this time in humans rather than other primates: "Calorie restriction (CR) enhances immune response and prolongs life span in animals. However, information on the applicability of these results to humans is limited. T-cell function declines with age. We examined effects of CR on T-cell function in humans. Forty-six overweight, nonobese participants aged 20–42 years were randomly assigned to 30% or 10% CR group for 6 months. Delayed-type hypersensitivity (DTH), T-cell proliferation (TP), and prostaglandin E2 (PGE2) productions were determined before and after CR. DTH and TP to T-cell mitogens were increased in both groups over baseline. However, number of positive responses to DTH antigens and TP to anti-CD3 reached statistical significance only after 30% CR. Lipopolysaccharide-stimulated PGE2 was reduced in both groups but reached statistical significance after 30% CR. These results, for the first time, show that 6-month CR in humans improves T-cell function." Mild CR provides only mild benefits, as we would expect.


Thoughts on Mortality Rates and Mechanisms

Here is an example of how looking at observable data on aging - such as mortality rates - can inform us of the nature of underlying mechanisms of aging: "What do you think are the odds that you will die during the next year? Try to put a number to it - 1 in 100? 1 in 10,000? Whatever it is, it will be twice as large 8 years from now. This startling fact was first noticed by the British actuary Benjamin Gompertz in 1825 and is now called the 'Gompertz Law of human mortality.' Your probability of dying during a given year doubles every 8 years. For me, a 25-year-old American, the probability of dying during the next year is a fairly miniscule 0.03% - about 1 in 3,000. When I'm 33 it will be about 1 in 1,500, when I'm 42 it will be about 1 in 750, and so on. By the time I reach age 100 (and I do plan on it) the probability of living to 101 will only be about 50%. This is seriously fast growth - my mortality rate is increasing exponentially with age. ... There is one important lesson, however, to be learned from Benjamin Gompertz's mysterious observation. By looking at theories of human mortality that are clearly wrong, we can deduce that our fast-rising mortality is not the result of a dangerous environment, but of a body that has a built-in expiration date." You might also look at the reliability theory of aging for a similar process of insight.