Fight Aging! Newsletter, July 29th 2013

July 29th 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!

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  • Considering Correlations Between Character and Dietary Intake
  • A Perspective on the Garbage Catastrophe of Aging
  • Do Very Small Embryonic-Like Stem Cells in Fact Exist in Adult Tissues?
  • Celebrities Reimagine Aging
  • The Rise of Cell Therapies to Repair Stroke Damage
  • Latest Headlines from Fight Aging!
    • Detrimental Effects From Dietary Antioxidant Supplementation
    • Hidden Depths and Wrong Conclusions in Demographic Studies of Human Mortality
    • Lifelong Calorie Restriction Increases Working Memory in Mice
    • Aiming at Immortality is Not a Waste of Time, as Some Propose
    • Lowered IGF-1 Levels Increase Maximum Mouse Life Span
    • A Discussion with Aubrey de Grey and Walter Bortz
    • Manipulating Mitochondrial Maintenance via NAD+
    • The Search For Biomarkers of Aging
    • New Results Suggest That Rapamycin Doesn't Slow Aging
    • Will Calorie Restriction Extend Life in Humans?


In statistical studies of health, considering the life histories, longevity, and mortality rates within a large group of individuals, researchers have found that calorie restriction and exercise have positive effects on long-term health that are large in comparison to all other positive influences measured to date. No widely available medical technology can yet grant even a sizable fraction of the additional healthy years of life that are available for free through the adoption of a better lifestyle. The most important goals in medicine - and all technology for that matter - for the next few decades involve making that last statement a thing of the past. That will involve finding ways to rejuvenate the old and extend healthy life far beyond what can be attained through today's technologies and techniques.

Meanwhile, the size of the influence of calorie restriction and exercise means that we have to eye every study in laboratory animals to see whether the researchers have accounted for differences between their groups. In human epidemiological studies, we have to ponder whether the researchers are correctly adjusting their results for these influences, or whether the associations that they identify between health or longevity and other characteristics are in fact just reflections of a deeper relationship with calorie intake or exercise.

In recent years a number of studies have claimed relationships between human mortality rates and various character traits. Researchers have standardized measures of personality, and those can be matched up with mortality in a range of different study data sets to show that some types of personality tend to live longer. One explanation is that this all comes to down to, say, ability to earn, and is thus just another facet of the standard issue correlation between wealth and longevity. Another theory is much the same, except replace wealth with conscientiousness and its effects on health maintenance.

But might it all be largely a matter of correlations with calorie intake? In a society in which calories are easy to come by, where in fact we need to actively refrain from eating more than is good for our long term health, the correlation between character and long term health might be much more pronounced than in past centuries. Yet this is only because calorie intake is such a strong determinant of the trajectory of health and mortality across a life span. So it is interesting to see people finding correlations between diet and personality:

Personality and Dietary Intake - Findings in the Helsinki Birth Cohort Study

We set out to study the associations between personality traits, resilience and food and nutrient intake in 1681 Finns in late adulthood. As hypothesized, neuroticism was associated with mainly poorer dietary quality as the intakes of fish and vegetables were lower and intake of soft drinks was higher, but this applied to women only. In line with our hypothesis, we observed extraversion being e.g. associated with a higher vegetable intake in women. Openness was associated with higher intakes of vegetables and fruits in both genders. Agreeable women showed favorable trends, as did conscientious women, the latter reporting e.g. a higher fruit intake. Some of these trends were further strengthened when testing subjects with resilient vs. non-resilient personality profiles; resilient women reported higher intakes of vegetables, fruits, fish, and dietary fiber and lower intake of alcohol. Our results were in line with our original study hypothesis and the associations were not due to age, educational attainment, or total energy intake.

Our result that neuroticism was associated with several unfavorable dietary intakes is consistent with two previous cross-sectional studies. One study in Japanese students found neuroticism to be associated with intakes of sweet and salty foods while a Scottish study found, high neuroticism to be associated with a traditional convenience diet (eating more tinned vegetables, meat pies, pasties and sausage rolls, puddings etc.) and low neuroticism to be associated with a Mediterranean-style diet. A recent Estonian study also found low neuroticism to be associated with a health aware dietary pattern. Our results are also in line with findings showing that high neuroticism is associated with obesity, metabolic syndrome and an increased risk for [cardiovascular_disease].

This study doesn't have anything to say about calorie level variations, but one might assume that where there is variation in constituents there will also be variation in calories.


We age because damage accumulates at the lowest levels of our biological structures, in and around the protein machinery of our cells. But an individual is not a static structure: we are not like buildings or cars because our machinery can repair and replace itself to an impressive degree. Cells accumulate enormous numbers of defects in their proteins and large component parts - such as mitochondria - on a day to day basis, and garbage in the form of metabolic waste products and broken or proteins accumulates constantly. The vast majority of these issues are repaired and removed extremely quickly.

The real downward slope in aging occurs when the mechanisms governing repair and maintenance start to fade. The advocates of programmed aging would say that this decline is the result of an unfortunate continuation of genetic programs that were necessary or advantageous in early life, but now become harmful. But most of the research community think that it's all still damage - it's just that the dynamic relationship between damage and health in a self-repairing system is much more complex than it is in a static structure. Damage accumulates, and some forms of damage cause a breakdown in the systems that remove damage: hence you wind up with what is known as the garbage catastrophe.

Researchers can explain genetic degenerative diseases that only manifest after a few decades of life in terms of this failure of maintenance: an individual that suffers far more damage than others due to an errant gene has cells that can keep up the pace in youth, but which lose the battle earlier in the process of declining repair with age. Neurodegenerative conditions like Parkinson's disease can be framed in this way as garbage catastrophes: the genetic associations determine who is being more rapidly damaged in some cell populations and thus more quickly overwhelmed.

Processes of cellular repair, such as autophagy, are considered important in how metabolism determines longevity: most methods of extending life by slowing aging in laboratory animals involve increased levels of autophagy, implying cells and cellular mechanisms that are less damaged for longer periods of time. Calorie restriction, for example, boosts autophagy. Scientists have been looking into increased autophagy as the basis for therapies for some years, as in this recent example of ongoing research into the genetic condition of Huntington's disease:

NIH-funded study finds that quickly clearing away damaged proteins may help prevent neurodegenerative disorders

Researchers investigated how cells deal with different forms of huntingtin, the protein involved in Huntington's. The mutant version of huntingtin is longer, and contains three building blocks of the protein repeated an abnormal number of times. These repeats in huntingtin are what cause it to misfold, eventually leading to neuron death and the symptoms of the disease.

The researchers found that the amount of time the mutant protein remained in the cell predicted neuronal survival: shorter mean lifetimes of mutant huntingtin were associated with longer neuronal survival. A shorter mean lifetime indicates that a protein does not remain in the cell for a long time, and that proteostasis is working effectively to clear it away. This suggests that improving proteostasis in Huntington's brains may improve neuronal survival.

To test this idea, the researchers activated Nrf2, a protein known to regulate protein processing. When Nrf2 was turned on, the mean lifetime of huntingtin was shortened, and the neuron lived longer. "Nrf2 seems like a potentially exciting therapeutic target. It is profoundly neuroprotective in our Huntington's model and it accelerates the clearance of mutant huntingtin. One surprising finding from these experiments was the significance of single cells' ability to clear mutant huntingtin. It turned out that this ability largely predicted their susceptibility, whether that neuron came from the most vulnerable region of the brain - the striatum - or the cortex, which is less vulnerable."

The findings indicate that the toxicity of the damaged proteins may cause neurodegeneration by interfering with the proteostasis system, affecting how quickly they are cleared from neurons. The researchers explored potential mechanisms behind differences in proteostasis. One way that cells normally get rid of proteins is through autophagy - a process in which proteins are packed up into spheres and then broken down. Results in this paper suggested that neurons increased the rate of autophagy when they sensed that the mutant form of huntingtin was accumulating, indicating the autophagy system may be a drug target.

"These findings provide evidence that our brains have powerful coping mechanisms to deal with disease-causing proteins. The fact that some of these diseases don't cause symptoms we can detect until the fourth or fifth decade of life, even when the gene has been present since birth, suggests that those mechanisms are pretty good."

Nrf2 is involved in the beneficial hormetic response to low levels of damage associated with calorie restriction, exercise, and the like. Interestingly long-lived naked mole rats have more Nrf2 in their cells, and the same is true of other long-lived species that appear to share a more effective cellular repair and maintenance response than their shorter-lived peers. Research of this nature all suggests that greatly boosted autophagy is a good thing to aim for as the basis for a therapy of general application - it's something that everyone should have turned on all the time.


In recent years a number of research groups have proposed that there exist populations of pluripotent stem cells in adult tissues, capable of forming any of the hundreds of different types of cell in the body. Different groups have different names for the cells they have found, but "very small embryonic-like stem cells" or VSELs is the name given by one of the more active researchers in this area. Greater confirmation or refutation of the existence of VSELs should also bias us one way or another for the various other researchers and their proposed pluripotent cell populations.

Why does this research matter? It is a matter of economics: if there is an easily accessible population of stem cells in every patient's skin that can be used to generate any type of cell in the body, then that will make a big difference to the pace at which regenerative therapies can be developed and deployed to the clinic, as well as making those therapies cheaper and faster. If, on the other hand, it turns out that adult tissues do not retain any sort of pluripotent stem cells, then it will require cell reprogramming to come to maturity in order to reach the same goals. All the other known and categorized stem cell populations in the adult body can be made to produce at best a couple of different types of cell, depending on their location and lineage.

Here, then, is a skeptical view on VSELs from researchers who have concluded that no such thing exists. Whenever you have a small number of researchers with differing opinions, the only thing to do is wait for more scientists to join in and produce further data:

A Wild Stem Cell Chase

The existence of very small embryonic-like stem cells (VSELs) has been hotly debated by scientists since they were first reported in mouse bone marrow in 2005. The cells were later identified in human blood and bone marrow as well, and have been proposed as a viable alternative to mouse and human embryonic stem cells (ESCs) in research and medicine. But a study published today [has] called the very existence of VSELs in question, with the senior author deeming them a "distraction."

Irving Weissman of Stanford University School of Medicine and his team set out to replicate the original finding of VSELs in mouse bone marrow, using the most rigorous protocols yet. They focused on identifying candidate VSELs by using the characteristics of size, phenotype, and pluripotency markers, but failed to find any cells that fit previous VSEL descriptions. The researchers found that the vast majority of events matching the estimated size of VSELs actually appeared to be artifacts, such as dead cells and debris. The team tested the remaining "exceedingly rare population" of cells that matched the VSEL profile for pluripotency markers without luck. "The claims about VSELs were not yet replicated by independent scientists. We redid the experiments as they have been described and could not confirm what was claimed."

Meanwhile, researchers continue to make progress on reprogramming of cells, but years lie between here and widespread use of therapies based on these technologies. The first early stage clinical trials using reprogrammed cells are only just starting now in Japan:

In the seven years since their discovery, induced pluripotent stem (iPS) cells have transformed basic research and won a Nobel prize. Now, a Japanese study is about to test the medical potential of these cells for the first time. Made by reprogramming adult cells into an embryo-like state that can form any cell type in the body, the cells will be transplanted into patients who have a debilitating eye disease. Masayo Takahashi, an ophthalmologist at the RIKEN Center for Developmental Biology in Kobe, Japan, plans to submit her application for the study to the Japanese health ministry next month, and could be recruiting patients as early as September.


A growing number of celebrity figures publicly support the work on human rejuvenation carried out by the SENS Research Foundation. That work is nothing less than building therapies to treat, halt, and reverse degenerative aging. Researchers employed by and associated with the Foundation labor to create biotechnologies that can repair the known and identified causes of degenerative aging, the low-level forms of persistent damage that occur in and around our cells.

SENS stands for the Strategies for Engineered Negligible Senescence, the research plan to take us from describing known forms of biological damage all the way to the therapies that can repair that damage. At this point the SENS research programs are detailed and fully realized: they draw from existing work that has taken place over the past few decades in laboratories around the world, and in some cases just a few years of a dedicated, fully funded research program would be enough to produce the first demonstration of specific forms of biological repair of aging in mice. Other portions of SENS need much more work - but in all cases, it is very clear just what has to be done to get to the point of a working therapy. The only hurdles remaining are funding and public support.

Thus we come to the support of celebrities and public figures, people who tend to straddle the worlds of wealth and attention, the two line items that are needed to speed and expand work on SENS. The SENS Research Foundation showcases some of their celebrity supporters on the carousel page linked below, such as Edward James Olmos, Ray Kurzweil, and Peter Thiel:

SENS Research Foundation Celebrity Reimagine Aging Campaign

If you want to change the way you think about aging, you've come to the right place. This page features exclusive thoughts on the topic from leading actors, musicians, celebrities, and visionaries. You'll see how everyone's views on aging are different - and how the research that we're funding right now draws from the most positive aspects of them all.

Aging today is like tuberculosis at the dawn of the 20th century: a blight upon the human condition, a scourge to be eradicated, and the medical community beginning to head in the right direction to perform that eradication. As SENS Research Foundation supporter Peter Thiel says of aging:

Almost every human being who has ever lived is dead. Solving this problem is the most natural, humane, and important thing we could possibly do.

If you happen to be one of the celebrities or public figures in the Fight Aging! audience, allow me to point out that you could do some good here. Join the Reimagine Aging initiative, and lend your voice and influence to supporting the work of the SENS Research Foundation, still the only organization on the planet to have undertaken the vital role of coordination, funding, and advocacy for the development of rejuvenation biotechnology. The future of medicine, including ways to reverse aging and rejuvenate the elderly, will arrive at the pace it is developed. Speeding that pace is a matter of greater public awareness, understanding, and of course funding. The more help we all give to this cause, the more likely it is that we will live to see our old age abolished, our suffering alleviated, and our healthy, active lives restored - and to know that we aided in saving billions of lives from an early, slow death.


A perfect world would include the means to prevent catastrophic failures of brain structure such as stroke from ever happening. One such means is a working implementation of the rejuvenation biotechnologies evisaged in detail in the SENS research plans. Strokes and other failures happen because tissue becomes damaged and frail. Remove that damage and the stroke risk of an old person would be that of a young person, which is to say very close to zero. Rejuvenation therapies lie a number of years in the future, however, where that number is very much determined by how much funding and support are dedicated to the right sort of research today. In the meanwhile, the present state of the art in medical technology, absent any way to greatly impact aging and the harm it causes, is to build better ways to clean up and restore more function after a stroke occurs.

The most promising lines of research in restorative therapies for stroke patients involve the manipulation and transplant of cells. Scientists are finding ways to spur native cells to greater feats of regeneration, or to bring in new cells that can do the job where native cells will not. I'm sure that you're all familiar with work on stem cell transplants of one form or another, for example, but there are many more strategies under development. On this topic a recent open access review notes the growth in clinical trials for stroke treatments in the past few years. At some point all of the promising work in the laboratory and all of the experience gained in treatments available via medical tourism will start to push its way into the highly regulated, expensive, slow-moving mainstream of clinical translation:

The Rise of Cell Therapy Trials for Stroke: Review of Published and Registered Studies

Stroke is responsible for 11.1% of all deaths, and is the second leading cause of death worldwide after ischemic heart disease. The injury produced by stroke is largely complete after 24-48 h, and neuroprotective therapies that must be administered within a time window such as 3-6 h are difficult to apply in clinical practice. Approximately 80% of all strokes are ischemic, and currently, tissue plasminogen activator (tPA) is the only pharmacological agent approved for treatment of acute ischemic stroke. However, tPA therapy has important limitations, notably the narrow therapeutic window of 4.5 h, which limits its use to a small minority (2% to 4%) of patients. Moreover, tPA prevents disability in only six patients per 1000 ischemic strokes, and does not reduce the mortality rate.

On the other hand, neurorestorative therapies, including cell therapies, seek to enhance regenerative mechanisms such as angiogenesis, neurogenesis, and synaptogenesis, and have been investigated extensively in the preclinical models of ischemia. Neurorestorative cell therapies can be grossly divided into endogenous or exogenous. Endogenous therapies are those that aim to stimulate, for example, bone marrow-cell migration to the blood stream, with pharmacological agents such as granulocyte-colony stimulating factor (G-CSF). The exogenous approach involves the injection of a variety of cells to produce structural or functional benefits. Although excellent reviews have been recently made on different aspects of cell therapies for stroke, there has been a dramatic increase in the number of published and registered trials in the past years that has not been comprehensively assessed.

Several preclinical studies have indicated that there is a structural and/or functional recovery after intracerebral, intra-arterial, and intravenous therapy with different cell types. Although clinical results with other ischemic diseases and preclinical studies for stroke are encouraging, there are still many questions regarding the possible mechanisms of action of the cells and the optimal treatment protocol. One of the main questions to be answered is related to the best cell type to be used in these patients. Further, aspects such as the mechanisms [that produce] improvements and the optimal treatment protocol are not yet fully understood and require further evaluation. Nevertheless, different clinical studies, the majority of them small, nonrandomized and uncontrolled, have now been reported and indicate that cell therapy seems safe, feasible, and potentially efficacious. The increasing number of ongoing studies, including large randomized double-blind studies, have the potential to determine the efficacy of cell therapy for stroke and to translate the preclinical findings into clinical practice.


Monday, July 22, 2013

At this point the general consensus is that dietary supplementation of antioxidant compounds is of either no benefit or mildly harmful to long term health. The only methods of extending life via the introduction of antioxidant compounds involve careful targeting to the mitochondria, such that damaging oxidant molecules generated there are swept up, but the oxidant molecules used in signaling processes elsewhere in cells and tissues are not. The benefits of exercise, for example, rest upon slightly raised levels of reactive oxygen species which can be blocked by high levels of antioxidants in the diet:

In older men, a natural antioxidant compound found in red grapes and other plants - called resveratrol - blocks many of the cardiovascular benefits of exercise. What is emerging is a new view that antioxidants are not a fix for everything, and that some degree of oxidant stress may be necessary for the body to work correctly. This pivotal study suggests that reactive oxygen species, generally thought of as causing aging and disease, may be a necessary signal that causes healthy adaptations in response to stresses like exercise. So too much of a good thing (like antioxidants in the diet) may actually be detrimental to our health.

We studied 27 healthy, physically inactive men around 65 years old for 8 weeks. During the 8 weeks all of the men performed high-intensity exercise training and half of the group received 250 mg of resveratrol daily, whereas the other group received a placebo pill (a pill containing no active ingredient). The study design was double-blinded, thus neither the subjects nor the investigators knew which participant that received either resveratrol or placebo.

"We found that exercise training was highly effective in improving cardiovascular health parameters, but resveratrol supplementation attenuated the positive effects of training on several parameters including blood pressure, plasma lipid concentrations and maximal oxygen uptake. We were surprised to find that resveratrol supplementation in aged men blunts the positive effects of exercise training on cardiovascular health parameters, in part because our results contradict findings in animal studies. It should be noted that the quantities of resveratrol given in our research study are much higher than what could be obtained by intake of natural foods."

Monday, July 22, 2013

Studies of human health are usually snapshots of a large population over a small fraction of their lives, gathering data so that researchers can use statistical methods to make inferences and identify correlations between lifestyles or genetics and health outcomes. There are many pitfalls here, not least of which is the tendency to lump together several groups with very different risks into one group, because the researchers didn't have the resources or the necessary data to dig deeper. For example, there is the business of risk levels between groups at various levels of alcohol consumption quoted below (wherein alcohol consumption habits are probably themselves strongly associated with lifestyle packages, wealth, conscientiousness, and other harder-to-measure line items that influence how well people tend to make use of medical services and how well they tend to take care of their health).

In an age of rapid progress in biotechnology, lifestyle choices like whether your drink a little or less than a little will soon become irrelevant to the general trajectory of your future health. Your future life span near-entirely depends on how fast rejuvenation therapies such as those featured in the Strategies for Engineered Negligible Senescence (SENS) proposals can be built. I point out this research by way of an example of one of the many systematic ways in which scientific work can be incomplete, misleading, or flawed, and encourage you think of it every time you look at another epidemiological study, so as to wonder what the authors there might be missing.

Multiple studies have shown that the likelihood of dying for people who drink increases as they consume more alcohol. Those same studies have shown that a person's mortality risk also increases at the other end of the spectrum - among people who choose not to drink at all - though the risk is still much less than for heavy drinkers. Some researchers have hypothesized that the increased mortality among nondrinkers could be related to the fact that light alcohol consumption - drinking, on average, less than one drink a day - might actually protect people from disease and reduce their stress levels.

But [other researchers] decided to examine whether characteristics of different subgroups of nondrinkers could explain the increased mortality risk. "Among nondrinkers, people have all sorts of background reasons for why they don't drink. We wanted to tease that out because it's not really informative to just assume that nondrinkers are a unified group." [The researchers] lied on data collected in 1988 by the National Health Interview Survey about the drinking habits of more than 41,000 people from across the United States. The researchers also had access to information about which respondents died between taking the survey and 2006. During the survey, nondrinkers were asked to provide their reasons for not drinking.

The research team divided nondrinkers into three general categories: "abstainers," or people who have never had more than 12 drinks in their lives; "infrequent drinkers," or people who have fewer than 12 drinks a year; and "former drinkers." Each category was further divided using a statistical technique that grouped people together who gave similar clusters of reasons for not drinking. The team then calculated the mortality risk for each subgroup compared with the mortality risk for light drinkers, and they found that the risks varied markedly.

Abstainers who chose not to drink for a cluster of reasons that included religious or moral motivations, being brought up not to drink, responsibilities to their family, as well as not liking the taste, had similar mortality risks over the follow-up period to light drinkers. Former drinkers, however, had the highest mortality risk of all nondrinkers. Former drinkers whose cluster of reasons for not drinking now included being an alcoholic and problems with drinking, for example, had a 38 percent higher mortality risk than light drinkers over the follow-up period. "So this idea that nondrinkers always have higher mortality than light drinkers isn't true. You can find some groups of nondrinkers who have similar mortality risks to light drinkers."

Tuesday, July 23, 2013

Calorie restriction is known to improve memory and slow the age-related decline of specific measures of brain health. Here is another example of research that reinforces the evidence for this benefit, as researchers start to spend more time on searching for differences in outcome in different implementations of calorie restriction:

Caloric restriction (CR) is argued to positively affect general health, longevity and the normally occurring age-related reduction of cognition. This issue is well examined, but most studies investigated the effect of short-term periods of CR. Herein, 4 weeks old female mice were fed caloric restricted for 4, 20 and especially for 74 weeks. CR mice received 60% of food eaten by their ad libitum (AL) fed littermates, and all age-matched groups were behaviorally analyzed.

The motor coordination, which was tested by rotarod/accelerod, decreased age-related, but was not influenced by the different periods of CR. In contrast, the age-related impairment of spontaneous locomotor activity and anxiety, both being evaluated by open field and by elevated plus maze test, was found aggravated by a lifelong CR. Measurement of cognitive performance with morris water maze showed that the working memory decreased age-related in AL mice, while a lifelong CR caused a better cognitive performance and resulted in a significantly better spatial memory upon 74 weeks CR feeding. However, a late-onset CR feeding in 66 weeks old mice did not ameliorate the working memory. Therefore, a lifelong CR seems to be necessary to improve working memory.

Tuesday, July 23, 2013

These days immortality is a lazy shorthand for vulnerable agelessness attained though medical technology: your body won't kill you while you have access to preventative therapies to treat aging, but falling pianos can still ruin your day. Aiming at the goal of indefinitely extended healthy lives is decried in some quarters, but the arguments marshaled against efforts to make the human condition better by eliminating the pain and suffering of degenerative aging have never looked all that coherent to me:

I was a bit perplexed, to say the least, when I read Big Think blogger John N. Gray's article "Immortality is a Waste of Time." His entire argument revolved around the notion that, because of unknown contingencies throughout life, the act of curtailing death's inevitability and infinity is thus a waste of time, money, thought and anxiety.

This is absurd. An absurdity flooded with fear-mongering imagery of our future, claiming the acts of planning for our possible deaths as being equivalent to "a society that is one of cryonic suspension, a freezer-centered society, a society in which we spend our thoughts, our desires, our passions, our incomes on tending freezers." Tending freezers, he says? Like we tend to our graveyards, our crematoriums, and mausoleums? Examples, I might add, to which wastes precious land to accommodate the bodies and/or ashes of our long-since-deceased (or soon-to-be-deceased) loved ones.

This notion that "history will go on," all while admitting that it "makes good sense to take care of your health, to try to remain healthy for as long as possible" and that "we should use the new technologies to enhance the mortal life we have," is contradictory and ahistorical. History most certainly went on, but then the goings-on of history were determined - not by a lack of care for what our future holds for us, but - by a global society who no longer saw it fit to merely live by age 30, or to go days without food, or to suffer from terrible diseases due to complete lack of medical aid and knowledge. Our society has spent centuries upon centuries fighting for a better world not just for themselves, but for those who'll come after them. Maybe our efforts won't lead to immortality in our lifetime. But then when is a good time to fight for it? Should we simply condemn our future relatives to a life - albeit one certainly going on - flooded with problems that could have been alleviated, if not addressed completely beforehand?

Wednesday, July 24, 2013

Insulin-like growth factor 1 (IGF-1) is one of the better studied components of metabolic pathways and mechanisms linked to longevity. Despite the many researchers and numerous years of work involved metabolism is so complex that there is still a very long way to go yet before the research community can establish complete understanding of what is actually going on in long-lived mutant mice with different levels of IGF-1. The cost and very slow pace of progress in the face of this complexity is one of the reasons why trying to slow aging by altering metabolism is a terrible choice of strategy for human life extension - we should instead focus on what we do understand well, which is how to repair the low-level cellular damage that causes aging, and keep the metabolism we have already.

Here is an example of continuing work on IGF-1 in mice, a confirmation of extended life, which is the sort of thing that keeps the grant funds coming for further efforts to figure out what is going on under the hood:

Reduced signaling through the IGF type 1 (IGF-1) receptor increases life span in multiple invertebrate organisms. Studies on mammalian longevity suggest that reducing levels of IGF-1 may also increase life span. However, the data are conflicting and complicated by the physiology of the mammalian neuroendocrine system.

We have performed life-span analysis on mice homozygous for an insertion in the Igf1 gene. These mice produce reduced levels of IGF-1 and display a phenotype consistent with a significant decrease in IGF-1. Life-span analysis was carried out at three independent locations. Although the life-span data varied between sites, the maximum life span of the IGF-1-deficient mice was significantly increased and age-specific mortality rates were reduced in the IGF-1-deficient mice; however, mean life span did not differ except at one site, where mean life span was increased in female IGF-1-deficient animals. Early life mortality was noted in one cohort of IGF-1-deficient mice.

The results are consistent with a significant role for IGF-1 in the modulation of life span but contrast with the published life-span data for the hypopituitary Ames and Snell dwarf mice and growth hormone receptor null mice, indicating that a reduction in IGF-1 alone is insufficient to increase both mean and maximal life span in mice.

Wednesday, July 24, 2013

A time-honored journalistic strategy is to put two interesting people with disparate views on their field in the same room to see what they have to say. In this case the subject is aging, longevity, and the prospects for extending healthy human life spans. The introductory blurb is quoted below, but the piece is long, with a lot of commentary from the participants - so click through and read the whole thing:

Bortz and de Grey have never met before, but they have a lot to talk about. I've asked them to come to the Tied House today - de Grey from eight blocks away, where his SENS (Strategies for Engineered Negligible Senescence) Research Foundation is headquartered; Bortz from nearby Stanford, where he teaches medicine - to discuss a subject that has obsessed both of them for decades: the process of aging, and how it may change in the decades ahead. Questions about the future of aging have been in the air lately. Are humans on the cusp of living to 120, 130, or more? What will aging look like in this new world of longevity? Will we just be adding 30, 40, 50 years to the end of life, or can we delay the process and lead normal lives to such advanced ages? Is 100 the new 60?

Neither Bortz nor de Grey is a stranger to publicity. A former co-chairman of the American Medical Association's Task Force on Aging and past president of the American Geriatrics Society, Bortz, a physician by training, is one of America's foremost experts on robust aging, having published more than 150 scientific articles on the subject. His "thesis," as he calls it, is that exercise is the key to extending the human life span. "We know enough to live 100 healthy years," Bortz says, "but we screw it up."

De Grey, meanwhile, has been a favorite subject for journalists since the early 2000s. As an undergraduate at Cambridge, he studied computer science; his specialty was artificial intelligence. But soon after graduation, he met and married Adelaide Carpenter, a Cambridge fruit-fly geneticist 19 years his senior, took over the genetics department's drosophila database, and immersed himself in the biology of aging. In 1999, de Grey published The Mitochondrial Free Radical Theory of Aging; a year later, Cambridge awarded him a Ph.D.

De Grey's new theories were grand. He believed that by dividing the diseases of old age into seven categories of cellular and molecular damage, and then by working to conquer each category through as-yet-undeveloped medical technologies, it would be possible to "cure" aging - not to stop it, or to slow it, but to repair and reverse it, the way one would restore an aging automobile, and to live indefinitely as a result. In 2000, de Grey co-founded the Methuselah Foundation, which awarded multimillion-dollar grants to scientists who extended the healthy life span of mice, and in 2009, the organization evolved into SENS, a nonprofit that sponsors and funds scientific rejuvenation research. Its major benefactor is Peter Thiel, the billionaire founder of PayPal.

Thursday, July 25, 2013

All sorts of maintenance processes operate in various parts of the cell. An important location is within the swarming herd of mitochondria, as damage there appears to be a significant cause of degenerative aging. Some forms of mitochondrial damage can evade the evolved means of repair and recycling, leading to dysfunctional mitochondria and dysfunctional cells that export harmful reactive compounds out into surround tissues. Can this process be slowed by boosting the operation of natural maintenance mechanisms, however? Arguably this is what happens in many of the methods demonstrated to extend life and slow aging in laboratory animals, such as calorie restriction, and here researchers are examining some of the relevant mechanisms in nematode worms:

NAD(+) is an important cofactor regulating metabolic homeostasis and a rate-limiting substrate for sirtuin deacylases. We show that NAD(+) levels are reduced in aged mice and Caenorhabditis elegans and that decreasing NAD(+) levels results in a further reduction in worm lifespan. Conversely, genetic or pharmacological restoration of NAD(+) prevents age-associated metabolic decline and promotes longevity in worms.

These effects are dependent upon the protein deacetylase sir-2.1 and involve the induction of mitonuclear protein imbalance as well as activation of stress signaling via the mitochondrial unfolded protein response (UPR(mt)) and the nuclear translocation and activation of FOXO transcription factor DAF-16. Our data suggest that augmenting mitochondrial stress signaling through the modulation of NAD(+) levels may be a target to improve mitochondrial function and prevent or treat age-associated decline.

Thursday, July 25, 2013

If we cannot accurately measure the progression of aging, then how do we establish whether a therapy under development meaningfully impacts aging? Animal studies will always precede human trials, and the necessary years will have been taken to measure changes in life span in short-lived species in the laboratory, but it is obviously out of the question to evaluate the effects on people by the wait-and-see method. A popular science piece here looks at the importance of the search for reliable ways to measure aging:

Don't look to online calculators of "biological age" for an answer. Those focus mainly on risk factors for diseases, and say little about normal aging, the slow, mysterious process that turns children to codgers. In fact, scientists are still hunting for biological markers of age that reliably register how fast the process is unfolding. Seemingly obvious candidates won't do. Wrinkles, for example, often have more to do with sun exposure than aging. Markers like age-related increases in blood pressure are similarly problematic, often confounded by factors unrelated to aging.

But recently researchers have identified some particularly good indicators of time's largely hidden toll on our bodies and how fast it's increasing. Experts on aging generally agree that acceptable biomarkers of aging should foretell the remaining life span of a middle-aged person more accurately than chronological age does. Further, they should offer a consistent picture of biological age. "Do those 50-year-olds with the best retention of immune function also tend to have the least cataracts, good sense of smell, least osteoporosis, lowest blood pressure and best memory?" Proposed biomarkers of aging haven't yet convincingly cleared these hurdles. But some provocatively telling ones have come to light.

Earlier this year [researchers] reported that a kind of molecular aging clock is embedded in our genomes whose speed can be measured via blood testing. The moving parts of the clock consist of chemical tags on DNA molecules that control whether genes are active in cells. The researchers found that the patterns of the tags, called epigenetic markers, predictably change with age. The scientists scrutinized around 485,000 of these tags in blood cells of 656 people aged 19 to 101. Some 70,387 tags were predictive of chronological age. Collectively these tags spell out "a signature for age that is largely not changed by disease or ethnic background." That means these markers may be less muddied by confounders than other factors tied to aging.

Friday, July 26, 2013

Contrary to earlier research wherein scientists concluded that rapamycin extends life by slowing aging, here another group proposes that the extended life observed in laboratory animals results from cancer suppression, and aging isn't greatly impacted. Drugs that can slow aging are in any case a sideshow, a line of research that will require decades and billions but is incapable of producing ways to rejuvenate the old. Only SENS and similar repair-based research programs have the potential to result in therapies that will extend the healthy lives of the elderly and restore their lost vigor and youth. So if the scientific community is going to spend the few decades between now and my old age working on new medicine, I'd rather they ditched the old-style drug discovery pipeline in favor of a research strategy that is actually likely to benefit me. As to the debate on rapamycin:

Rapamycin is used in recipients of organ transplants, as it keeps the immune system in check and can consequently prevent rejection of the foreign tissue. In 2009, US scientists discovered another effect: Mice treated with rapamycin lived longer than their untreated counterparts. "Rapamycin was the first drug shown to extend maximal lifespan in a mammalian species. This study has created quite a stir. We wanted to address if rapamycin slows down aging in mice or, alternatively, if it has an isolated effect on lifespan - without broadly modulating aging."

"Our results indicate that rapamycin extends lifespan, but it has only limited effects on the aging process itself. Most aging traits were not affected by rapamycin treatment. Although we did observe positive effects on some aging traits, such as memory impairments and reduced red blood cell counts, our studies showed that similar drug effects are also seen in young mice, indicating that rapamycin did not influence these measures by slowing aging, but rather via other, aging-independent, mechanisms."

The researchers believe that such aging-independent drug effects also underlie rapamycin's effect on lifespan. "We assume that the lifespan of mice is extended because rapamycin inhibits tumor formation. This is a well-known rapamycin effect, which we were able to confirm. Cancer is the leading cause of death in the relevant mouse strains. Rapamycin, therefore, seems to have isolated effects on specific life-limiting pathology, but lacks broad effects on aging in mice."

"Generally speaking, our studies show that a number of different parameters have to be considered when assessing the efficacy of possible anti-aging interventions. The interpretation of the data depends heavily on the overall picture of findings. Lifespan measures alone are not a reliable indicator of anti-aging effects. This makes the search for anti-aging medicines tedious, but it is also very promising, because such substances could open up new possibilities for medicine. However, this is still some way off."

Friday, July 26, 2013

Here is a commentary on what is known of the effects of calorie restriction in humans, and the prospects for determining whether or not it actually extends life in our species, from one of the foremost researchers in the field:

Calorie Restriction (CR) without malnutrition is the most powerful nutritional intervention that has consistently been shown to increase maximal and average lifespan in a variety of organisms, including yeasts, worms, flies, spiders, rotifers, fish and rodents. Far from merely stretching the life of an old, ill and weak animal, CR extends longevity by preventing chronic diseases, and by preserving metabolic and biological functions at more youthful-like state. In rodents, the CR-mediated preventive effects are widespread with major reductions in the occurrence and/or progression of cancer, nephropathy, cardiomyopathy, obesity, type 2 diabetes, neuro-degenerative disease, and several autoimmune diseases.

Whether or not CR without malnutrition will extend lifespan in humans is not known yet, but accumulating data indicate that moderate CR with adequate nutrition has a powerful protective effect against the development of obesity, type 2 diabetes, inflammation, hypertension and cardiovascular disease, which are major causes of morbidity, disability and mortality. In humans calorie restriction without malnutrition also results in a consistent reduction in circulating levels of growth factors, anabolic hormones, adipokines and inflammatory cytokines, which are associated with an increased risk of some of the most common types of cancer.

Moreover, CR in these individuals resulted in an amelioration of two well-accepted markers of cardiovascular aging, i.e. left ventricular diastolic function and heart rate variability. These data indicate that CR exerts direct systemic effects that counter the expected age-associated changes in myocardial stiffness and autonomic function so that LV diastolic function and heart rate variability indexes in CR individuals are similar to those of individuals 20 years younger on a typical Western diet. Consistently, we recently found that CR without malnutrition results in dramatic changes of the human skeletal muscle transcriptional profile that resemble those of younger individuals.

More studies are needed to understand how macro- and micro-nutrients, endurance exercise, and other environmental and psychological factors interact with CR in modulating metabolic and molecular pathways that regulate health and longevity. Randomized, CR-controlled, long-term survival studies in humans will never be performed because of obvious problems with long-term compliance and costs of such a long study. Nonetheless, we hope that by following the health status of individuals practicing long-term CR without malnutrition, in particular of those who are now in their 70s and 80s, we could gain soon some information about the effects of CR on successful aging and healthy longevity in humans as well. Because we have detailed information about their close relatives' disease and survival histories, if we observe that as the [CR practitioners] age, they don't develop any of the metabolic abnormalities and/or chronic diseases typical of their parents/siblings, and live substantially longer than their relatives, this will be the best available proof that CR works in humans.


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