Fight Aging! Newsletter, October 28th 2013

October 28th 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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  • Comparing the Longevity of Growth Hormone Mutants
  • A Review of Theories on the Causes of Alzheimer's Disease
  • A Review of the Thyroid Gland in Aging
  • A Few More Thoughts on Public Disinterest in Living Longer
  • Recent Negativity on the Prospect of Extended Healthy Life
  • Latest Headlines from Fight Aging!
    • Making Old Stem Cells Functionally Young, Part II
    • Genetic Stabilization of Transthyretin, Cerebrovascular Disease, and Life Expectancy
    • An Update on Using DNA Methylation to Measure Age
    • Mixed Results When Infusing Young Immune Cells Into an Old Mouse
    • Towards Reversal of Vascular Calcification
    • Transdifferentiation of Fat Cells Into Liver Cells and a Demonstration of Partial Liver Regeneration
    • Insulin-Like Signaling and Longevity in Flies
    • ANMT-1 and Nematode Longevity
    • Using Yeast to Search for Drugs to Target Alpha-Synuclein in Parkinson's Disease
    • Considering Epigenetic Drift in Aging


Despite more than a decade of finding numerous ways to slow aging in mice, the longest-lived genetically altered mice are still those that lack the genes for growth hormone receptor (GHR), one of the earliest demonstrations of a longevity mutation. They are small and have very little body fat, and as a result have to be carefully husbanded because they are vulnerable to cold - they wouldn't do well in the wild, but are otherwise healthy. These mice live 60-70% longer then their unmodified peers. But why?

A decade of research has not produced a definitive answer to that question, but rather a set of plausible contributions and theories proposed with varying amounts of confidence and supporting evidence. This mutation has a sweeping effect on metabolism, altering many areas thought to be important in aging and longevity. Producing any of these individual changes in isolation, so as to evaluate its effect, has proven challenging: metabolism is a web of linked systems and feedback loops, and changing any one item will cause reactions in all linked subsystems and mechanisms. One of the few definitive successes here is the removal of visceral fat: it is possible to surgically remove some of that fat from mice and show extension of life as a result, so we can reasonably conclude that some portion of the GHR knockout effect results from lower levels of visceral fat.

There are other ways to impact growth hormone beyond removing its receptor. Researchers can eliminate the gene for growth hormone itself, for example, or as in the work noted below they can add a gene for a growth hormone receptor antagonist (GHA), producing a protein that to some degree blocks the normal interaction between growth hormone and its receptor. Comparing the results on mouse metabolism and life span produced by these varied approaches might help to identify the importance of different contributing mechanisms to the life extension effect of GHR knockout.

Repression of GH signaling: One extended life to live!

Noteworthy is the fact that GHA mice do not experience significantly longer lifespans as do other mouse lines with a reduction in the GH/IGF-1 axis, such as the aforementioned GHR-/- mice. As a result, GHA mice have not been as extensively studied. Regardless, comparing the phenotype of GHA mice with other long-lived lines, such as GHR-/- mice, should reveal the most important traits caused by reduced GH action that are responsible for lifespan extension. An important distinction between GHA mice and GHR-/- mice is that the GHA does not completely inhibit GH signaling, while inhibition of GH signaling in GHR-/- mice is complete. Thus, we have generated two dwarf mice each with either low or no GH induced intracellular signaling (and each with low levels of IGF-1) yet only one has extended longevity.

Again, what molecular mechanisms account for this difference in lifespan between these two dwarf lines? GHA mice generally have a phenotype intermediate between that of control and GHR-/- mice, especially as it relates to size, readouts of the GH/IGF-1 axis and measures of glucose homeostasis. For example, GHA mice are dwarf, but not as dramatic as seen in GHR-/- mice. As compared to controls, circulating IGF-1 are reduced in both lines but by only ~25-40% in GHA mice as opposed to more than 80% in GHR-/- mice. While GHR-/- mice are extraordinarily insulin sensitive, glucose homeostasis is moderately improved in young GHA mice with low to normal plasma levels of glucose and insulin. However, insulin levels deteriorate with advancing age in male GHA mice. Perhaps the more marginal decreases in IGF-1 or the lack of dramatic alterations in glucose metabolism are sufficient in GHA mice to curb significant gains in longevity.

Interestingly, while dwarf throughout life, the body weight of male GHA mice gradually catches up to that of control mice with advancing age [due to] marked increases in adipose tissue. Where do GHA mice deposit their adipose tissue and could that be relevant to longevity? Like GHR-/- mice, GHA mice display dramatic increases in the subcutaneous fat depot. However, unlike GHR-/- mice, intra-abdominal fat pads (including visceral depots) become enlarged with advancing age in GHA mice, which may contribute to their deterioration in glucose homeostasis over time.

So here again is something to point to the accumulation of visceral fat as a bad thing for health and longevity. This is one of the few aspects of our biochemistry that we can reliably do something about today, and some portion of the demonstrated long-term health benefits of exercise and calorie restriction probably stems from the presence of lesser amounts of visceral fat tissue. Studies show that maintaining even a modest excess of body fat has a detrimental effect on future health and life expectancy.


Alzheimer's disease is perhaps the most studied form of age-related neurodegeneration. About 40% of the yearly budget of the US National Institute on Aging goes towards research into Alzheimer's disease, for example, and that is just the easily discovered funding. Where there is work on treating Alzheimer's rather than further investigating it, that research tends to focus on clearing clumps and fibrils of misfolded proteins known as amyloid. Alzheimer's is accompanied by a characteristic build up of amyloid beta, which many researchers think is the proximate cause of the harm the condition does to the brain. You might look at ongoing attempts to direct a patient's immune system to clear amyloid from the brain, for example.

Neural biochemistry is enormously complex, however, and there is plenty of room for uncertainty and argument over the root causes of Alzheimer's, how it progresses, and exactly which mechanisms are damaging and destroying brain cells. Why do some people suffer Alzheimer's while others do not, for example, even though we all appear to progress down the same path general of amyloid buildup and cellular damage? Here is an open access review paper that surveys the current range of plausible theories:

What causes alzheimer's disease?

Ever since the first description of pre-senile dementia by Alois Alzheimer in 1907, the presence of cognitive impairment together with the formation of senile plaques (SP) and neurofibrillary tangles (NFT) have been regarded as the [defining] features of Alzheimer's disease (AD). Many theories as to the cause of AD have [been] proposed. It is not the intention to discuss every theory but to concentrate on those most likely to be involved. Hence, the theories are discussed in eight categories: (1) acceleration of aging, (2) degeneration of anatomical pathways, including the cholinergic and cortico-cortical pathways, (3 environmental factors such as exposure to aluminium, head injury, and malnutrition, (4) genetic factors including mutations of amyloid precursor protein (APP) and presenilin (PSEN) genes, and allelic variation in apolipoprotein E (Apo E), (5) a metabolic disorder resulting from mitochondrial dysfunction, (6) vascular factors such as a compromised blood brain barrier, (7) immune system dysfunction, and (8) infectious agents. This review discusses the evidence for and against each of these hypotheses and develops a general theory as to the cause of AD.

That AD may be an accelerated form of natural aging is based on the observation that the many pathological changes in AD are similar to those present in normal aging apart from their severity. Hence, in cognitively normal brain, there is an age-related reduction in brain volume and weight, enlargement of ventricles, and loss of synapses and dendrites in selected areas. Accompanying these changes are the characteristic pathological features of AD, including SP and NFT. Studies of Aβ deposition have also demonstrated a clear overlap between AD and normal aging. It was concluded that it was not possible to distinguish early-stage AD from normal aging at post-mortem. Similarly, SP have been observed in 60% of normal elderly cases, albeit at lower density than in AD. Moreover, [researchers have] concluded that there could be a 'continuum' of pathological change from elderly non-demented brains, early stage AD, to advanced AD.

Whether NFT occur as a result of normal aging is more controversial, [however]. Two further aging processes may be involved in AD. First, an age-related breakdown of myelin, although other studies suggest that myelin loss occurs late in AD and is secondary to neuronal degeneration. Second, the loss of cells in the locus caeruleus (LC), which provides noradrenaline to the cortex [and] stimulates microglia to suppress production of Aβ.

These studies suggest that the differences between AD and the normal elderly are largely quantitative rather than qualitative and there may be a 'continuum' of pathological change connecting these cases. Nevertheless, the distribution of the pathology may differ in AD and control brain, being more localised to areas of the temporal lobe in aging and with a more extensive spread into the hippocampus and cortical association areas in AD. An important question, therefore, is whether AD is an exacerbation of normal aging resulting from enhanced spread of the pathology along anatomical pathways.


The thyroid gland produces a number of hormones that regulate metabolism, and as such both it and these hormones tend to show up in studies of aging and longevity. Variations in the operation of metabolism affect the pace of aging in individuals, and somewhere in the associated long chain of cause and effect can be found the thyroid and its activities.

One of the challenges inherent in building therapies based on data gathered about the operation of metabolism and variations between individuals is that it is hard to say whether what you are proposing to alter is a cause or a consequence. It is also presently a real challenge to discover all of the meaningful consequences of any particular metabolic alteration. So researchers can point to data and argue that longer-lived people tend to have characteristically similar levels of certain thyroid hormones, but you can't jump right from that to an assumption that trying to replicate this particular configuration of protein levels in other people will be beneficial.

This open access paper is a quick tour through published research, present consensus, and open questions regarding the thyroid and aging. A few of the more directly relevant portions are quoted below, but the whole thing is worth at least skimming for the examples of other associations with specific age-related conditions:

Thyroid and Aging or the Aging Thyroid? An Evidence-Based Analysis of the Literature

There has been long standing controversy about the thyroid function test results in the elderly. Serum thyroid-stimulating hormone (TSH), free thyroxine (T4), and free triiodothyronine (T3) concentrations change with aging. There is an increasing wealth of data suggesting that serum TSH levels increase with age, particularly after 70 years, but the data on free T4 is conflicting. This might reflect reduced end organ sensitivity, reduced turnover, and clearance, a genetic trait conferring a survival benefit or a combination of factors. In addition, no clear benefit is seen in treating a high TSH on a multitude of outcomes in the elderly. In fact, there is a possibility that treatment in the very elderly may lead to adverse outcomes. On the other hand, a low TSH has been associated with worse outcomes in the older age group.

The Leiden 85+ study showed that higher TSH concentrations and lower free thyroxine levels were associated with a survival benefit. In this study, participants with low levels of TSH at baseline had highest mortality rate, and participants with high TSH levels and low FT4 levels had the lowest mortality rate. The authors speculated that lower thyroid function may lead to lower metabolic rate which in turn could cause caloric restriction. Lower metabolic rate and caloric restriction have both been shown to be associated with improved survival in several animal studies.

There have been few recent studies exploring longevity with raised TSH and familial/genetic basis for this phenomenon. Data from the Leiden Longevity Study showed that when compared with their partners, the group of offspring of nonagenarian siblings showed a trend toward higher serum TSH levels in conjunction with lower free T4 levels and lower free T3 levels. In their extension to this study, they found that lower mortality in the parents of nonagenarian siblings was associated with higher serum TSH levels, lower free serum T4 levels, and lower free T3 levels in the nonagenarian siblings.

The comment on thyroid function leading to calorie restriction is interesting, because the relationship has been shown to go the other way: calorie restriction alters thyroid hormone levels in ways that appear similar to what is seen in longer-lived people. All these things are feedback loops in a connected system, of course, so it's quite possible to have cause and consequence in both directions.


When it comes to public discussion of extending healthy life spans through medical science, the tide is slowly turning. As a serious scientific goal, this used to be mocked when it was ever discussed at all. Now healthy life extension is discussed both seriously and more often. But it is still the case that the majority of the public puts little thought into the intersection of aging and progress in medicine, and when pushed for an opinion express disinterest in living longer. This is obviously problematic for those of us who do see the possibilities in longevity science: radical life extension could be achieved within our lifetimes given enough funding and support, but that support is slow in arriving.

There are a range of opinions as to why the broader public doesn't leap on the idea of living longer, healthier lives with great enthusiasm and approval. It is somewhat odd when seen from a logical perspective as, after all, there is widespread grassroots support for the development of better treatments for age-related diseases. The average person on the street thinks that progress is being made on the prevention and cure of heart disease, cancer, and so on, and that this is a good thing. But ask them about aging and extended life and you'll hear that nothing should be done, and they are set to die on the same schedule as their parents.

Most advocates for the development of rejuvenation therapies think that the biggest issue is that most people still think that living longer will mean being older for longer rather than being younger for longer - that it will mean more misery and pain and increasing decrepitude. Yet this has never been the message propagated by the scientific community: scientists are working on means to make people younger for longer, or to reverse aging so as to restore youthful vigor and capabilities to the old, and have always presented their research in terms of health and youth. "Older for longer" is a myth, and probably not even something that could be achieved at all, were someone foolish enough to try, but it persists nonetheless.

Why We Should Look Forward To Living To 120 And Beyond

Surprisingly, most people do not want to have their life spans extended. In my opinion, this pessimistic view stems from several factors. First, when forming a conscious and subconscious opinion about life expectancy, most people use as benchmarks their parents' and grandparents' life spans, and the national average. The line of thought is usually: "I am 40, my grandmother lived to 92, my dad is 70, and I heard that the average is about 78, so I should live to somewhere between 80 and 95. But I am not sure if I want to live that long, because my grandmother was very frail in her later years."

These perceptions are fostered by researchers who look at historic trends and project only marginal increases, or even decreases, in future life expectancy. These researchers predict that recent behavioral changes, like high-calorie diets and sedentary lifestyles, as well as pollution and other environmental factors, will outweigh life-extending advances in biomedical sciences. But the past 20 years have demonstrated that those relying on historical trends to make predictions about science and technology are often proven wrong.

People may also believe an extended life span will extend frailty and boredom in old age. But biomedical advances are not all the same. The current paradigm in biomedical research, clinical regulation and healthcare has created a spur of costly procedures that provide only marginal increases late in life. The vast percentage of lifetime healthcare costs today are spent in the last few years of patients' lives, increasing the burden on the economy and society and further contributing to the negative image of life extension. In the near future, however, the focus of biomedicine will shift to extending healthy, productive lives and keeping people young and occupied for as long as possible.

The preventive approaches available today, including improved diet and exercise and more advanced early diagnostics, may have the potential to add 10 to 20 years to our life spans. But future generations will more likely rely on biomedical interventions to prevent the loss of functionality with age and to maintain or even improve their performance on all levels. The lowest-hanging fruit is regenerative medicine, which will likely allow most of the organs in the body to be replaced or rejuvenated.


There has been more discussion of the future of medicine and human longevity in the print media of late. I attribute this to a combination of Google's announcement of their Calico initiative and an ongoing low-key advertising campaign run by Prudential, wherein that company seeks to differentiate itself through displaying an awareness of the potential for large increases in human life span in the years ahead.

There is also a larger than usual fraction of articles that take longevity science and medical development seriously, which is pleasant. Though I'm sure that this is at least partially because it is a lot harder to do otherwise without looking like an idiot these days, given that ever more scientists are willing to talk in public about extending health life spans. It is much easier to find scientific literature, reviews, and interviews with researchers in which they talk favorably about a future of longer lives. Beliefs and opinions change step by step, one increment at a time. That said, while it's harder to dismiss the science out of hand nowadays, there are still plenty of people willing to tell us that it is better for countless millions to die horribly and slowly than for any of those people to survive to risk being bored sometimes, or that old people are too dangerous to be permitted to live any longer:

Why No One Actually Wants to Live Forever

Depression runs high among retirees, and not just because of reduced income - in fact, the baby boomers who have recently retired are living a life of relative luxury compared with those of us still a few decades away. No, the reason they get depressed is because when you're retired, it is easy to feel like you have nothing to live for anymore, no purpose, nothing to get up for, no reason to even get dressed. In a word, they are bored.

What we forget when we focus on extending our lifespan as long as possible is that things make us happy because they are rare, finite, and therefore valuable and precious. Diamonds. Newborns. Laughter. Great first dates. Great third dates. Sunshine. (I live in London. Trust me, sunshine is very rare and very finite.) Make these things available to everyone all the time, and they would lose their glow, become mundane.

The problem with longevity? Old people.

Now consider radical life extension. It means that decision-making power, and economic and political authority, will be vested in a generation that is already obsolete and growing more so. People who find Facebook's and Twitter's popularity incomprehensible and more than slightly spooky will be making employment decisions based on outdated concepts of public and private personas. The young and innovative will be held at bay, prevented from creating new information forms and generating cultural, institutional, and economic breakthroughs. And where death used to clear the memory banks, there I stand ... for 150 years.

The social order of today versus that of the Roman Empire are remarkable for their similarities, not their differences, despite the much greater length of life we expect to enjoy today. Positions change, people change, and leaders are overturned on a timescale that is small compared to our life spans - and that timescale is much the same as it was two thousand years ago. I don't see it changing in the slightest if people lived twice as long as they do now, as the factors leading to social change have very little to do with overall length of life, proceeding as they do on a month-to-month and year-to-year basis, driven by what people want here and now, not ten years or twenty years away.

All in all it is odd that people are so willing to hold up such airy constructs of speculation as those above as viable arguments against efforts to prevent the very concrete cost of aging: the death of tens of millions every year and the ongoing suffering of hundred of millions more. But not every op-ed and article is negative these days; there are signs that more and more people are becoming accustomed to and even supportive of the idea that living longer in good health is the future, and that medical research aimed at increasing human longevity is a good and deserving cause.


Monday, October 21, 2013

Last year researchers uncovered one of the controlling portions of the process by which the hematopoietic stem cells (HSCs) that form blood decline with age. This is a part of the age-related decline of all stem cell types: researchers who subscribe to a programmed view of aging see this a part of the program of aging, a primary cause of frailty and degeneration. Researchers who theorize that aging is a non-programmed accumulation of damage, the more mainstream view at this time, see the decline of stem cell capacity as an evolved response to rising levels of cellular and molecular damage, one that evolved in order to reduce the risk of cancer arising from the actions of damaged cells.

This difference of interpretation is important. In programmed aging world, the right thing to do given the discovery of such a mechanism is to build a therapy to adjust the levels of critical controlling proteins in order to restore a youthful mode of operation - and this is all you have to do in order to halt this part of degenerative aging. In aging-as-damage world, trying to make this change happen is a largely futile endeavor, and certainly not what should be the primary focus of the research community. Such a therapy may produce short-term benefits, as it will temporarily minimize a secondary contribution to the frailty of aging. However, since it fails to address the underlying damage that causes aging and stem cell decline, it is like revving up a worn engine. The outcome will most likely be a greatly raised risk of cancer.

In any case, here is an update on last year's research. The scientists are making progress in following the chain of proteins involved in shutting down stem cell activity in older tissues:

"Although there is a large amount of data showing that blood stem cell function declines during aging, the molecular processes that cause this remain largely unknown. This prevents rational approaches to attenuate stem cell aging. This study puts us significantly closer to that goal through novel findings that show a distinct switch in a molecular pathway is very critical to the aging process." The pathway is called the Wnt signaling pathway, a very important part of basic cell biology that regulates communications and interactions between cells in animals and people. Disruptions in the pathway have been linked to problems in tissue generation, development and a variety of diseases.

Analyzing mouse models and HSCs in laboratory cultures, the scientists observed in aging cells that a normal pattern of Wnt signaling (referred to in science as canonical) switched over to an atypical mode of activity (called non-canonical). They also noticed that the shift from canonical to non-canonical signaling was triggered by a dramatic increase in the expression of a protein in aged HSCs called Wnt5a. When the researchers decided to test this observation by intentionally increasing the expression of Wnt5 in young HSCs, the cells began to exhibit aging characteristics.

Interestingly, the dramatic increase of Wnt5a in aged HSCs activated another protein called Cdc42, which turned out to be critical to stem cell aging. Cdc42 is the same protein the scientists targeted in their 2012 study. In that study, the authors showed that pharmacologically inhibiting Cdc42 reversed the aging process and rejuvenated HSCs to be functionally younger.

The researchers decided that for the current study, they would conduct experiments to see how blocking Wnt5a would affect HSC aging. To do so, they deleted Wnt5a from the HSCs of mice. They also bred mice to lack two functioning copies of the Wnt5a gene, which in essence blocked the protein's function in the HSCs of those animals. Deleting Wnt5 from cells functionally rejuvenated the HSCs. In mice bred to lack two functioning copies of the Wnt5a gene, the animals exhibited a delayed aging process in blood forming stem cells.

Monday, October 21, 2013

Regular readers will no doubt recall that TTR amyloidosis, also known as senile systemic amyloidosis, is a prime suspect for the mechanism that limits human life span to the 110-120 range. Based on evidence from autopsies performed on supercentenarians, those who through luck, genes, and lifestyle manage to survive past the age of 110, these outliers are largely slain by a buildup of amyloid deposits that leads to clogging of blood vessels and ultimately to heart failure.

Transthyretin, or TTR is a protein involved in the transport of a thyroid hormone through the bloodstream. It produces amyloid when it misfolds, something that only becomes threatening in the young for the few unfortunate individuals who inherit a faulty TTR gene. There is some research aimed at producing a therapy for this inherited form of TTR amyloidosis, and the SENS Research Foundation has funded it with an eye to also producing ways to address the age-related form. If there was a good way to periodically clear this amyloid from our tissues, that is all that would need to be done for most people in order to eliminate this very slow-moving contribution to degenerative aging.

Here is an eye-opening piece of research that shows a significant correlation between a minor variant of the TTR gene and life expectancy differences driven by cardiovascular disease and other risks. The effect is surprisingly large for a minor genetic variation, from what I recall of similar research in recent years, and I'd certainly want to see this result replicated before taking it as read. It is still a good argument for bumping up the priority for research into amyloid clearance therapies, though one could argue that perhaps other mechanisms are also at work here, since levels of thyroid hormones seem to be important in longevity:

Transthyretin can cause amyloidosis attributable to destabilization of transthyretin tetramers in plasma. We tested the hypothesis that genetic stabilization of transthyretin associates with reduced risk of vascular disease and increased life expectancy. We included 68,602 participants from 2 prospective studies of the general population. We genotyped for 2 stabilizing genetic variants in the transthyretin gene (TTR), R104H and T119M, and determined the association of genotypes with plasma levels of transthyretin, measures of thyroid function, risk of vascular disease, and life expectancy.

During a mean follow-up of 32 years, 10,636 participants developed vascular disease. We identified 321 heterozygotes for T119M (frequency, 0.47%); R104H was not detected. First, mean plasma transthyretin and thyroxine levels were increased by 17% and 20%, respectively, in heterozygotes versus noncarriers, demonstrating functionality of this variant in the general population. Second, corresponding hazard ratios were 0.70 for all vascular diseases, 0.85 for cardiovascular disease, 0.45 for cerebrovascular disease, 0.47 for ischemic cerebrovascular disease, and 0.31 for hemorrhagic stroke. The cumulative incidence of cerebrovascular disease as a function of age was decreased in heterozygotes versus noncarriers.

Third, median age at death from all causes, from vascular and cerebrovascular diseases, and after diagnosis of vascular disease, and median age at diagnosis of vascular disease, was increased by 5 to 10 years in heterozygotes versus noncarriers.

Tuesday, October 22, 2013

The search for ways to measure both chronological and biological age from tissue samples is producing interesting early results. Chronological age is how old you are by the clock, but biological age is a measure of how rapidly the processes of degenerative aging are progressing in your case: different people slide down the slippery slope at somewhat different rates, whether because of genes, luck, or lifestyle choices. DNA methylation is one line of research: it occurs across the whole genome and changes with age as metabolism reacts to rising levels of cellular damage. Combining measurements of the methylation of many different genes seems to produce fairly good results when it comes to identifying the age of individuals and tissues:

"To fight aging, we first need an objective way of measuring it. Pinpointing a set of biomarkers that keeps time throughout the body has been a four-year challenge," said Steve Horvath, a professor of human genetics at the David Geffen School of Medicine at UCLA and a professor of biostatistics at the UCLA Fielding School of Public Health. "My goal in inventing this age-predictive tool is to help scientists improve their understanding of what speeds up and slows down the human aging process."

To create his age predictor, Horvath focused on a naturally occurring process called methylation, a chemical modification of one of the four building blocks that make up our DNA. He sifted through 121 sets of data collected previously by researchers who had studied methylation in both healthy and cancerous human tissue. Gleaning information from nearly 8,000 samples of 51 types of tissue and cells taken from throughout the body, Horvath charted how age affects DNA methylation levels from pre-birth through 101 years. For the age predictor, he zeroed in on 353 markers linked to methylation that change with age and are present throughout the body.

Horvath tested the predictive tool's effectiveness by comparing a tissue's biological age to its chronological age. When the tool repeatedly proved accurate in matching biological to chronological age, he was thrilled - and a little stunned. "It's surprising that one could develop a predictive tool that reliably keeps time across the human anatomy. My approach really compared apples and oranges, or in this case, very different parts of the body - including brain, heart, lungs, liver, kidney and cartilage."

Tuesday, October 22, 2013

The immune system declines with age, its army of cells capable of meeting new threats diminishing in number and capacity. One possible form of palliative therapy for immune system aging, intended to produce benefits to the condition of the patient without addressing the underlying causes of this degeneration, is to create large numbers of new immune cells and infuse them into the patient. It is well within the present capabilities of the stem cell research community to grow new immune cells from a patient's stem cells - and indeed this has been accomplished for some years in various forms of clinical trial.

Here is a study that tries this sort of approach in mice, but with mixed results: no harm is done, and it looks like the therapy is having the intended effect under the hood, but equally the most obvious measure of whether it's doing any good in terms of boosted immune response isn't reliably improved either. More work is needed here:

Transfusion of autologous leukocytes after prolonged storage has been proposed as a means of rejuvenating the immune system of older individuals. The rationale for this approach is that age related immune decline is associated with a diminished pool of naïve T cells following atrophy of the thymus and reduction in thymic output. The presence of high levels of naïve T cells within the blood of young individuals could provide a boost to the immune system of an older "self" through a rejuvenation of the naïve T cell pool.

However what remains unresolved is whether the cells could be incorporated effectively into the T cell pool of the host and whether effectors could be generated. Using CD45 congenic mice in our experiments we show that the transfusion of young donor cells into older congenic host animals leads to their successful incorporation into the peripheral T cell pool. When the recipients were challenged with influenza virus, specific effector CD8 cells were generated which were of both host and donor origin.

This would suggest that the environment provided by the host is not lacking and that effectors could be generated in an immune response to antigenic challenge. However the functional response as judged by viral load would appear to be variable, muted in some animals and showing greater effectiveness in others. Our results reveal that although there was a five-fold difference between the lowest and the highest number of cells transferred, at the time of assay there was no major difference in the numbers of donor cells in the hosts when compared with the numbers injected. Our experiments would suggest that there appears to be no direct correlation between the number of cells injected and the number of cells present within the host at the time of assay, implying that cell dose was not a critical factor in incorporation into the peripheral T cell pool.

Wednesday, October 23, 2013

Calcification appears to be one of the causes of increasing vascular stiffness with age, a form of functional deterioration in blood vessels that contributes to numerous age-related conditions. Here, researchers investigate means to remove this calcium:

Elastin-specific medial vascular calcification, termed "Monckeberg's sclerosis," has been recognized as a major risk factor for various cardiovascular events. We hypothesize that chelating agents, such as disodium ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), and sodium thiosulfate (STS) might reverse elastin calcification by directly removing calcium from calcified tissues into soluble calcium complexes.

We assessed the chelating ability of EDTA, DTPA, and STS on removal of calcium from hydroxyapatite (HA) powder, calcified porcine aortic elastin, and calcified human aorta in vitro. We show that both EDTA and DTPA could effectively remove calcium from HA and calcified tissues, while STS was not effective. The tissue architecture was not altered during chelation. In the animal model of aortic elastin-specific calcification, we further show that local periadventitial delivery of EDTA loaded in to nanoparticles regressed elastin-specific calcification in the aorta. Collectively, the data indicate that elastin-specific medial vascular calcification could be reversed by chelating agents.

Wednesday, October 23, 2013

This is the age of discovery for cellular control: cells are just complex machines, and with the right environment and chemical instructions the behavior and even type of a cell lineage can be radically changed. A lot of time and funding presently goes into discovering how to achieve these goals, as greater control over cells opens up many new vistas in medicine. At present, and in parallel to research into induced pluripotency as a path to generating any type of cell from easily obtained patient samples, such as skin or fat tissue, scientists are exploring the possibilities of transdifferentiation. At least some types of cell can be coerced into directly becoming other types of cell, without having to pass through an embryonic-like pluripotent stage, and researchers are becoming better at making this happen:

Scientists have developed a fast, efficient way to turn cells extracted from routine liposuction into liver cells. The scientists performed their experiments in mice, but the adipose stem cells they used came from human liposuction aspirates and became human, liver-like cells that flourished inside the mice's bodies.

Liver cells are not something an adipose stem cell normally wants to turn into. The [researchers] knew it was possible, though. Another way of converting liposuction-derived adipose stem cells to liver-like cells had been developed in 2006. But that method, which relies on chemical stimulation, requires 30 days or longer and is inefficient; it could not produce enough material for liver reconstitution. Working with induced pluripotent (iPS) cells takes even longer; they must first be generated from adult cells before they can be converted. Using a different technique [known] as spherical culture [researchers] were able to achieve the conversion within nine days with an efficiency of 37 percent, as opposed to the vastly lower yield obtained with the prior method (12 percent) or using iPS cells.

When they had enough cells, the investigators tested them by injecting them into immune-deficient laboratory mice that accept human grafts. Only the livers of these mice contained an extra gene that would convert the antiviral compound gancyclovir into a potent toxin. When these mice were treated with gancyclovir, their liver cells died off quickly. At this point the investigators injected 5 million [of the newly generated cells] into the mice's livers. Four weeks later, the investigators examined the mice's blood and found the presence of a protein (human serum albumin) that is only produced by human liver cells and was shown to be an accurate proxy for the number of new human liver cells in these experimental mice's livers. The mice's blood had substantial human serum albumin levels, which nearly tripled in the following four weeks. These blood levels correspond with the repopulation of roughly 10-20 percent of the mice's pre-destroyed livers by new human liver tissue.

Blood tests also revealed that the mice's new liver tissue was discharging its waste-filtration responsibility. Examination of the livers themselves showed that the transplanted cells had integrated into the liver, expressed surface markers unique to mature human hepatocytes and produced multi-cell structures required for human bile duct formation.

Thursday, October 24, 2013

Insulin-like signaling is one of the better studied portions of the overlap between metabolism and aging, but even this alone is an enormously complex system. There is much left to discover:

Evolutionarily conserved insulin/insulin-like growth factor signaling (IIS) pathway governs growth and development, metabolism, reproduction, stress response, and longevity. In Drosophila, eight insulin-like peptides (DILPs) and one insulin receptor (DInR) are found, ended by dilp genes. Temporal, spatial, and nutrient regulation of DIPLS provides potential mechanisms in modulating IIS. Compensatory transcriptional regulatory mechanisms and functional redundancy that exist among DILPs make it difficult to dissect out their individual roles.

While the brain secretes DILP2, 3, and 5, fat body produces DILP6. Identification of factors that influence dilp expression and DILP secretion has provided insight into the intricate regulatory mechanisms underlying transcriptional regulation of those genes and the activity of each peptide. Studies involving loss-of-function dilp mutations have defined the roles of DILP2 and DILP6 in carbohydrate and lipid metabolism, respectively. While DILP3 has been implicated to modulate lipid metabolism, a metabolic role for DILP5 is yet to be determined.

Loss of dilp2 or adult fat body specific expression of dilp6 has been shown to extend lifespan, establishing their roles in longevity regulation. The exact role of DILP3 in aging awaits further clarification. While DILP5 has been shown associated with dietary restriction (DR)-mediated lifespan extension, contradictory evidence that precludes a direct involvement of DILP5 in DR exists. This review highlights recent findings on the importance of conserved DILPs in metabolic homeostasis, DR, and aging, providing strong evidence for the use of DILPs in modeling metabolic disorders such as diabetes and hyperinsulinemia in the fly that could further our understanding of the underlying processes and identify therapeutic strategies to treat them.

Thursday, October 24, 2013

Sirtuin research continues despite disappointing results in mammals, and here leads to a new piece in the puzzle of linked protein mechanisms, and a novel way to extend life in nematode worms:

Sirtuins, a family of histone deacetylases, have a fiercely debated role in regulating lifespan. In contrast with recent observations, here we find that overexpression of sir-2.1, the ortholog of mammalian SirT1, does extend Caenorhabditis elegans lifespan.

Sirtuins mandatorily convert NAD(+) into nicotinamide (NAM). We here find that NAM and its metabolite, 1-methylnicotinamide (MNA), extend C. elegans lifespan, even in the absence of sir-2.1. We identify a previously unknown C. elegans nicotinamide-N-methyltransferase, encoded by a gene now named anmt-1, to generate MNA from NAM.

Disruption and overexpression of anmt-1 have opposing effects on lifespan independent of sirtuins, with loss of anmt-1 fully inhibiting sir-2.1-mediated lifespan extension. MNA serves as a substrate for a newly identified aldehyde oxidase, GAD-3, to generate hydrogen peroxide, which acts as a mitohormetic reactive oxygen species signal to promote C. elegans longevity. Taken together, sirtuin-mediated lifespan extension depends on methylation of NAM, providing an unexpected mechanistic role for sirtuins beyond histone deacetylation.

Friday, October 25, 2013

Misfolded forms of alpha-synuclein have been identified as a proximate cause of dying brain cells in Parkinson's disease (PD), and so there is considerable interest in ways to remove this protein or block its mode of action. The research reported here is a good example of the platforms that researchers build in order to search for compounds that might be developed into drugs for this sort of task. Even when a specific protein or mechanism has been identified, at the present time it isn't yet possible to step directly to the answer and design the right molecule for the job. It remains more efficient to explore tens of thousands of candidates in the lab.

In the search for compounds that might alter a protein's behavior or function - such as that of alpha-synuclein - drug companies often rely on so-called target-based screens that test the effect large numbers of compounds have on the protein in question in rapid, automated fashion. Though efficient, such an approach is limited by the fact that it essentially occurs in a test tube. Seemingly promising compounds emerging from a target-based screen may act quite differently when they're moved from the in vitro environment into a living setting.

To overcome this limitation [researchers have] turned to phenotypic screens in which candidate compounds are studied within a living system. Yeast cells - which share the core cell biology of human cells - serve as living test tubes in which to study the problem of protein misfolding and to identify possible solutions. Yeast cells genetically modified to overproduce alpha-synuclein serve as robust models for the toxicity of this protein that underlies PD.

In a screen of nearly 200,000 compounds, [researchers] identified one chemical entity that not only reversed alpha-synuclein toxicity in yeast cells, but also partially rescued neurons in the model nematode C. elegans and in rat neurons. Significantly, cellular pathologies including impaired cellular trafficking and an increase in oxidative stress, were reduced by treatment with the identified compound. [Researchers then examined] neurons derived from induced pluripotent stem (iPS) cells generated from Parkinson's patients. The cells and differentiated neurons (of a type damaged by the disease) were derived from patients that carried alpha-synuclein mutations and develop aggressive forms of the disease. [The researchers] used the wealth of data from the yeast alpha-synuclein toxicity model to clue them in on key cellular processes that became perturbed as patient neurons aged in the dish. Strikingly, exposure to the compound identified via yeast screens [reversed] the damage in these neurons.

Friday, October 25, 2013

Epigenetics is the study of mechanisms that cause changes in gene expression. Genes encode proteins, and gene expression is the complex multi-step process by which proteins are built from that blueprint. Changes in the amount of any specific protein in circulation or in a specific location in a cell can result in significant changes in the operation of metabolism, altering the operation of cellular machinery that in turn feeds back to further change gene expression. Our biology is a massively complex web of feedback loops and linkages between genes and proteins.

DNA methylation is of the mechanisms by which gene expression is altered. It involves the addition of a chemical tag to a gene. The pattern of DNA methylation changes with aging, a process sometimes called epigenetic drift, and some of those changes are characteristic enough to be used as a measure of age.

While a number of key signalling pathways (e.g. mTOR signalling) and biological processes (e.g. telomere attrition) affecting lifespan have been identified, other theories have argued that aging results mainly from accumulated molecular damage. Most likely, aging is determined by a complex cross-talk between multiple biological effects. Molecular damage itself can take many forms, including somatic DNA mutations and copy-number changes.

The advent of novel biotechnologies, allowing routine genome-wide quantitative measurement of epigenetic marks, specially DNA methylation, have recently demonstrated that age-associated changes in DNA methylation, a phenomenon now known as "epigenetic drift", may play an equally important role in contributing to the aging phenotype. Indeed, like telomere attrition, epigenetic drift has been associated with stem cell dysfunction, disease risk factors and common age-related diseases, such as cancer and Alzheimer's. Apart from extensive experimental work supporting a role for DNA methylation in aging, computational network biology approaches have recently shed further light into the potential role of epigenetic drift. For instance, one study has shown that drift appears to target WNT signalling, a key pathway in stem-cell differentiation and already known to be deregulated with age.

A more recent study mapped epigenetic drift occurring in gene promoters onto a human protein interactome and observed that most of the changes happen at genes which occupy peripheral network positions, i.e. those of relatively low connectivity. Although developmental transcription factors make up a significant proportion of "drift genes", the observed topological effect was not entirely driven by this enrichment. Crucially, the topological properties of genes undergoing epigenetic drift were highly distinctive from those which have been associated with modulating longevity, those undergoing age-related changes in expression, or those somatically mutated in age-related diseases like cancer. Moreover, essential housekeeping genes, many of which occupy highly central positions in the interactome, appear protected from epigenetic drift.

Although the overall functional significance of epigenetic drift remains to be established, a few instances of epigenetic drift causing silencing of key transcription factors have already been reported. Thus, it is plausible that epigenetic drift may gradually affect differentiation programs through functional deregulation of key lineage determining transcription factors, leading to well-known observations such as myeloid skewing of the aged hematopoietic system. Epigenetic drift affecting key transcription factors may further increase predisposition to age-related diseases like cancer, by locking stem cells into states of self-renewal, and causing tissues to exhibit an increased cellular plasticity and diversity, a likely prerequisite for neoplastic formation.


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