Fight Aging! Newsletter, March 18th 2013

March 18th 2013

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!



- Scientific Approaches and the Creation of Human Longevity
- Considering the Sirtuin Approach
- Considering the mTOR Approach
- Video: Aubrey de Grey on Defeating Aging
- Discussion
- Latest Headlines from Fight Aging!
    - On Mortality Rates and Life Expectancy
    - Testing Neurons Created From Skin Cells in Primates
    - Malate and Nematode Lifespan
    - Global Futures 2045 Conference in June
    - Calorie Restriction Reduces Levels of Astrogliosis
    - More on Lipid Metabolism and Inherited Longevity
    - On Rapamycin's Detrimental Effects
    - Correlations Between Status and Longevity are Due to Other Factors
    - Being Overweight Harms the Heart Over the Long Term
    - A Different Approach To Biological Replacements for Teeth


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

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

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

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


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

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

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

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

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


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

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

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

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


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


The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!



Friday, March 15, 2013
Here is a piece to act as fuel for people who like to argue policy and don't look much beyond the now. I think this is chiefly interesting for the potential support it gives to lifestyle differences between the genders as a noteworthy contributing cause to the fact that women live longer. Otherwise, it reinforces the point that differences in life expectancy at birth between regions or over time is not all that relevant to the intersection of medicine and aging - more attention should be given to statistics for life expectancy at 50 or 60. "Higher mortality rates among Americans younger than 50 are responsible for much of why life expectancy is lower in the United States than most of the world's most developed nations. The research [found] that excess mortality among Americans younger than 50 accounted for two-thirds of the gap in life expectancy at birth between American males and their counterparts and two-fifths between females and their counterparts in the comparison countries. Most of the excess mortality of those younger than 50 was caused by noncommunicable diseases, including perinatal conditions, such as pregnancy complications and birth trauma, and homicide and unintentional injuries including drug overdose, a fact that she said constitutes a striking finding of the study. "These deaths have flown under the radar until recently. This study shows that they are an important factor in our life expectancy shortfall relative to other countries."" You get further in life by comparing what you have to what is possible, not with what other people have. But relativism of status, circumstances, and possessions is deeply set into the human mind. It's ever a struggle to get people to look beyond what is to see what might be.

Friday, March 15, 2013
An example of an application of induced pluripotent stem cells moving closer to use in humans. The transplant of new brain cells is a potential treatment for a range of neurodegenerative conditions: "Scientists have transplanted neural cells derived from a monkey's skin into its brain and watched the cells develop into several types of mature brain cells. [After] six months, the cells looked entirely normal, and were only detectable because they initially were tagged with a fluorescent protein. Because the cells were derived from adult cells in each monkey's skin, the experiment is a proof-of-principle for the concept of personalized medicine, where treatments are designed for each individual. And since the skin cells were not "foreign" tissue, there were no signs of immune rejection - potentially a major problem with cell transplants. "When you look at the brain, you cannot tell that it is a graft. Structurally the host brain looks like a normal brain; the graft can only be seen under the fluorescent microscope." The transplanted cells came from induced pluripotent stem cells (iPS cells), which can, like embryonic stem cells, develop into virtually any cell in the body. iPS cells, however, derive from adult cells rather than embryos. In the lab, the iPS cells were converted into neural progenitor cells. These intermediate-stage cells can further specialize into the neurons that carry nerve signals, and the glial cells that perform many support and nutritional functions. This final stage of maturation occurred inside the monkey."

Thursday, March 14, 2013
The smaller and shorter lived the animal, the easier it is to extend its life in the laboratory. This is in part because more experiments can run at lower cost, but also because it seems that many of the evolved, shared mechanisms for adjusting the pace of aging or degree of tissue maintenance in response to environmental circumstances (e.g. calorie restriction) have a larger effect in shorter-lived species. Any given mechanism for lengthening life span can be triggered or partially triggered or gently influenced in numerous ways. A lot of present research is focused on enumerating these many methods, and then matching them up to the few known underlying mechanisms for lengthening life. So we see research publications like this one: "Although mitochondrial-derived oxygen radicals have been questioned as the main driving force for the aging process, changes in mitochondrial metabolism almost certainly play a role. Dietary restriction (DR), which extends lifespan, also delays the aging-induced electron transport chain dysfunction in rodents. DR increases the NAD/NADH ratio in many tissues, which stimulates mitochondrial tricarboxylic acid (TCA) cycle dehydrogenases that utilize NAD as a cofactor. The increased TCA cycle function likely necessitates increased anaplerosis, important for longevity. Alteration of mitochondrial TCA cycle function influences lifespan in C. elegans. Malate, the tricarboxylic acid (TCA) cycle metabolite, increased lifespan and thermotolerance in the nematode C. elegans. The increased longevity provided by malate addition did not occur in fumarase (fum-1), glyoxylate shunt (gei-7), succinate dehydrogenase flavoprotein (sdha-2), or soluble fumarate reductase F48E8.3 RNAi knockdown worms. Therefore, to increase lifespan, malate must be first converted to fumarate, then fumarate must be reduced to succinate by soluble fumarate reductase and the mitochondrial electron transport chain complex II. Lifespan extension induced by malate depended upon the longevity regulators DAF-16 and SIR-2.1. Malate supplementation did not extend the lifespan of long-lived eat-2 mutant worms, a model of dietary restriction. Malate and fumarate addition increased oxygen consumption, but decreased ATP levels and mitochondrial membrane potential suggesting a mild uncoupling of oxidative phosphorylation. Malate also increased NADPH, NAD, and the NAD/NADH ratio. Fumarate reduction, glyoxylate shunt activity, and mild mitochondrial uncoupling likely contribute to the lifespan extension induced by malate and fumarate by increasing the amount of oxidized NAD and FAD cofactors."

Thursday, March 14, 2013
The next conference put on by the 2045 Initiative will be held in mid-June in New York. The initiative is backed by a wealthy Russian businessman and aims to move from biological bodies and minds to machine bodies and minds as rapidly as possible. This is not my favored path to greatly enhanced longevity - largely for reasons of efficiency and speed, as I've outlined in the past - but it is at least promising that the world's high net worth individuals are starting to see that they can do a great deal to change the state of human longevity. The costs of doing so have fallen to the point at which one billionaire could push the research and development community in the right direction by following the standard playbook for encouraging the foundation and growth of a research and development community. Every movement has its quirks, and it remains to be seen where the focus on engineering of human culture and building bridges to religious communities, wrapped into the work on artificial bodies, will take the 2045 initiative. I'd certainly be more comfortable with more of a focus on technology and less on societal engineering involving religion. The latter has a lot of failure modes, amply demonstrated throughout history in many large and small groups: "The second international Global Future 2045 congress will take place on 15-16 June 2013 at the Lincoln Center in New York, and will be focused on discussion of a new evolutionary strategy for humanity aimed at overcoming the 21st century's civilization challenges. The strategy is based on carrying out two revolutions: spiritual and sci-tech. We believe this is the only way to overcome existing crises. At the congress, a vision will be presented for the spiritual transformation of humanity, and new technologies will be demonstrated which are likely to form the basis of the sci-tech revolution. The congress will also showcase our Avatar science mega-project, aimed at accelerating the creation of technologies enabling a gradual transition from our biological bodies to an increasingly advanced artificial carrier of the human self. The first GF2045 congress took place in Moscow in February 2012. Its main goal was a discussion of global threats and opportunities arising from the development of new technologies, and the formulation of recommendations for the realization of the optimal scenario for the future with regard to the expected usage of these technologies. In the world of international science, this was the first time at this level and in this form, that not only the key directions of innovations in the coming decades were examined, but also their ethical and philosophical aspects. The main goals of the 2045 Initiative: the creation and realization of a new strategy for the development of humanity which meets global civilization challenges; the creation of optimale conditions promoting the spiritual enlightenment of humanity; and the realization of a new futuristic reality based on 5 principles: high spirituality, high culture, high ethics, high science and high technologies.

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

Wednesday, March 13, 2013
Another specific benefit of calorie restriction is enumerated in this primate study, one that suggests a generally lower level of damage to the brain is taking place in calorie restricted individuals. The lack of impact on β-amyloid is interesting, however, given that calorie restriction has been shown to slow near every other measurable aspect of aging: "While moderate calorie restriction (CR) in the absence of malnutrition has been consistently shown to have a systemic, beneficial effect against aging in several animals models, its effect on the brain microstructure in a non-human primate model remains to be studied using post-mortem histopathologic techniques. In the present study, we investigated differences in expression levels of glial fibrillary acid protein (GFAP) and β-amyloid plaque load in the hippocampus and the adjacent cortical areas of 7 Control (ad libitum)-fed and 6 CR male rhesus macaques using immunostaining methods. CR monkeys expressed significantly lower levels (~30% on average) of GFAP than Controls in the CA region of the hippocampus and entorhinal cortex, suggesting a protective effect of CR in limiting astrogliosis. These results recapitulate the neuroprotective effects of CR seen in shorter-lived animal models. There was a significant positive association between age and average amyloid plaque pathology in these animals, but there was no significant difference in amyloid plaque distribution between the two groups. Two of the seven Control animals (28.6%) and one of the six CR animal (16.7%) did not express any amyloid plaques, five of seven Controls (71.4%) and four of six CR animals (66.7%) expressed minimal to moderate amyloid pathology, and one of six CR animals (16.7%) expressed severe amyloid pathology. That CR affects levels of GFAP expression but not amyloid plaque load provides some insight into the means by which CR is beneficial at the microstructural level, potentially by offsetting the increased load of oxidatively damaged proteins, in this non-human primate model of aging."

Wednesday, March 13, 2013
Some characteristic differences in lipid metabolism are associated with greater human longevity; this is one of the few markers of an inherited predisposition to longevity that clearly shows up in multiple population studies. Here is more detail on this topic: "Middle aged offspring of nonagenarians, as compared to their spouses (controls) show a favorable lipid metabolism marked by larger LDL particle size in men and lower total triglyceride levels in women. To investigate which specific lipids associate with familial longevity, we explore the plasma lipidome by measuring 128 lipid species [in] 1526 offspring of nonagenarians (59 years ± 6.6) and 675 (59 years ± 7.4) controls from the Leiden Longevity Study. In men, no significant differences were observed between offspring and controls. In women however, nineteen lipid species associated with familial longevity. Female offspring showed higher levels of ether phosphocholine (PC) and sphingomyelin (SM) species (3.5-8.7%) and lower levels of phosphoethanolamine PE (38:6) and long-chain triglycerides (TG) (9.4-12.4%). The association with familial longevity of two ether PC and four SM species was independent of total triglyceride levels. In addition, the longevity-associated lipid profile was characterized by a higher ratio of monounsaturated (MUFA) over polyunsaturated (PUFA) lipid species suggesting that female offspring have a plasma lipidome less prone to oxidative stress. Ether PC and SM species were identified as novel longevity markers in females, independent of total triglycerides levels. Several longevity-associated lipids correlated with a lower risk of hypertension and diabetes in the Leiden Longevity Study cohort. This sex-specific lipid signature marks familial longevity and may suggest a plasma lipidome with a better antioxidant capacity, lower lipid peroxidation and inflammatory precursors, and an efficient beta-oxidation function."

Tuesday, March 12, 2013
Rapamycin extends life in mice via mechanisms that seem at least somewhat complementary to those of calorie restriction, but it isn't the sort of thing you'd want to take haphazardly given the other effects it has. Its primary use in medical practice is as an immunosuppressant, for example. Research teams have made inroads in splitting out the bad from the good, but there's a way to go there yet. "The evolutionarily conserved target of rapamycin (TOR) signaling controls growth, metabolism, and aging. In the first robust demonstration of pharmacologically-induced life extension in mammals, longevity was extended in mice treated with rapamycin, an inhibitor of mechanistic TOR (mTOR). However, detrimental metabolic effects of rapamycin treatment were also reported, presenting a paradox of improved survival despite metabolic impairment. How rapamycin extended lifespan in mice with such paradoxical effects was unclear. Here we show that detrimental effects of rapamycin treatment were only observed during the early stages of treatment. These effects were reversed or diminished in mice treated for 20 weeks, with better metabolic profiles, increased oxygen consumption and ketogenesis, and markedly enhanced insulin sensitivity. Thus, prolonged rapamycin treatment lead to beneficial metabolic alterations, consistent with life extension previously observed. Our findings provide a likely explanation of the "rapamycin paradox" and support the potential causal importance of these metabolic alterations in longevity."

Tuesday, March 12, 2013
We humans are complex creatures, and variations in our longevity in any given generation can be shown to correlate with all sorts of societal line items: status, wealth, intelligence, education, happiness, and so forth. But what are the mechanisms that create these correlations? Here is a small piece of research to suggest that status, at least, doesn't seem to have a significant and consistent effect in and of itself - that correlation must be based on other related items, such as wealth or intelligence: "Research has long linked high socioeconomic status with better health and lower mortality. But what's remained unclear is whether this association has more to do with access to resources (education, wealth, career opportunity, etc.) or the glow of high social status relative to others. Scholars call the latter "relative deprivation." To tease apart these factors, a team of investigators [studied] Baseball Hall of Fame inductees, Emmy Award winners, and former Presidents and Vice Presidents, comparing each to nominated losers in the same competition or election. The result: There were no consistent advantages for winners. The association between winning and longevity is sometimes positive, sometimes negative, and sometimes nonexistent, though the specifics are revealing. Overall, the results suggest that access to resources and opportunity is more important than relative status. "The relative deprivation theory would predict that losers would consistently be at a disadvantage for health and longevity compared to winners, but this is not what we see." A more likely explanation [is] that the advantages and disadvantages of winning depend on the mix of opportunities and stresses that they bring. "Our findings provide an important correction to an overemphasis on relative deprivation as an explanation of health inequalities. Relative deprivation likely plays some role in health inequalities, but it is not as important as the life circumstances and opportunities that result from one's socioeconomic position.""

Monday, March 11, 2013
Carrying excess fat tissue for years in youth and mid-life is associated with a greater risk of age-related disease and a shorter life expectancy down the line. An increased level of chronic inflammation is one of the reasons why this is the case, but here is a closer look at another of the mechanisms involved: "Results of this longitudinal study found that people who carry excess weight over their lifetime are much more likely to have increases in left ventricular mass and relative wall thickness - both strong and independent predictors of cardiovascular morbidity and mortality. In this instance, timing is indeed everything; the earlier someone becomes overweight, the greater the increase in the heart's mass later in life. "Being overweight in your 20s can have detrimental effects on the heart 40 years in the future, especially if you keep the weight on over the years. It's probably the wrong attitude to think 'I know I'm overweight now, but I'll lose the weight later' because the longer you spend overweight, the greater the weight of your heart muscle. And we know from other studies that even if we take away or account for high blood pressure, diabetes or other risk factors for heart disease, somebody with a bigger heart muscle is more likely to have a heart attack, die or have other problems, such as stroke." Researchers tracked the body mass index (BMI) of 1,653 men and women at different points in their lives to examine the effects of being overweight on the structure of the heart. BMI is a simple measure of the body's fat using a calculation of weight to height. People who were considered overweight, with a BMI of 25 to 29.9, or obese, with a BMI of 30 or above, had the heaviest hearts. [Few], if any, studies have been able to look at this question over such a long duration. He and his team drew from 44 years of data. Strikingly, the heart was 7 percent heavier for those who were overweight beginning in their 20s compared to those who only became overweight in their 60s."

Monday, March 11, 2013
Tissue engineering of teeth has so far focused on growing new teeth and then implanting them - but you don't necessarily have to produce an exact replacement if you can produce something that works: "Research towards achieving the aim of producing bioengineered teeth - bioteeth - has largely focussed on the generation of immature teeth (teeth primordia) that mimic those in the embryo that can be transplanted as small cell 'pellets' into the adult jaw to develop into functional teeth. Remarkably, despite the very different environments, embryonic teeth primordia can develop normally in the adult mouth and thus if suitable cells can be identified that can be combined in such a way to produce an immature tooth, there is a realistic prospect bioteeth can become a clinical reality. In this new work, the researchers isolated adult human gum tissue from [patients], grew more of it in the lab, and then combined it with the cells of mice that form teeth. By transplanting this combination of cells into mice the researchers were able to grow hybrid human/mouse teeth containing dentine and enamel, as well as viable roots. "Epithelial cells derived from adult human gum tissue are capable of responding to tooth inducing signals from embryonic tooth mesenchyme in an appropriate way to contribute to tooth crown and root formation and give rise to relevant differentiated cell types, following in vitro culture. These easily accessible epithelial cells are thus a realistic source for consideration in human biotooth formation. The next major challenge is to identify a way to culture adult human mesenchymal cells to be tooth-inducing, as at the moment we can only make embryonic mesenchymal cells do this.""



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