FIGHT AGING! NEWSLETTER
November 4th 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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- Less Frailty in Ames Dwarf Mice and Calorie Restricted Mice
- Crowdfunding Success for Mitochondrial Gene Therapy Project
- Questioning Telomere Dynamics as a Predictor of Mortality
- Another Spotlight on SENS Research Foundation Interns
- Prospects for Regeneration of Organs Without Stem Cells
- Latest Headlines from Fight Aging!
- Work on a Cytomegalovirus Vaccine
- Ongoing Work on an Alzheimer's Vaccine
- Intramuscular Fat as a Contributing Cause of Sarcopenia
- Proposing the Cross-Link EGGL as a Target in Aging Tissue
- Apolipoprotein D Expression Correlates With Reduced Age-Related Neurodegeneration
- Examining the Epigenetic Effects of Exercise
- Reactiving Dormant Stem Cells in the Aging Heart
- Evaluating Exercise and Health is Harder Than You Might Think
- GHRH Knockout Mice Live 50% Longer, and Longer Still With Calorie Restriction
- Hardening of Arteries Linked to Plaques in Brain
LESS FRAILTY IN AMES DWARF MICE AND CALORIE RESTRICTED MICE
Ames dwarf mice are genetically engineered to lack growth hormone, and as a result are small, comparatively vulnerable to cold, and live much longer than their peers. The biochemistry of these mice has a number of similarities to that of calorie restricted mice, who also live much longer than their peers. Study of these and other forms of long-lived mice is shedding light on an overlapping collection of mechanisms that link the operation of metabolism with differences in the pace of degenerative aging. The hope here is that at some point this will lead to therapies to produce similar benefits in we humans, but most researchers think that such a result is comparatively distant from where we are now. The changes produced in mice through either growth hormone knockout or calorie restriction are sweeping, and it will be challenging to prove that any artificial alteration of human metabolism on the same scale is safe over the long term.
Nothing is stopping you from practicing calorie restriction, of course, and indulging in your own self-created sweeping and beneficial change to the operation of your metabolism. The human studies show that the benefits to a basically healthy individual exceed any other presently available strategy for improving long-term health. But the rules and chances of a positive outcome are very different when you want to try altering human genes and biological processes with medical technologies. Nonetheless, the enumerated benefits are good enough to keep research funds flowing, albeit at a very low level in comparison to fields such as stem cell medicine or cancer research.
Prevention of Neuromusculoskeletal Frailty in Slow-Aging Ames Dwarf Mice: Longitudinal Investigation of Interaction of Longevity Genes and Caloric Restriction
The hypopituitary Ames Dwarf Mouse was the seminal example of single-gene regulation of mammalian longevity. They are deficient in the production of growth hormone (GH), thyroid stimulating hormone, and prolactin. The deficiency in somatotrophic signaling results in mice that are approximately half the size (length or weight) of their littermate controls. These mice outlive their normal littermate counterparts by approximately 40-60%. These results of longevity have been confirmed on different diets, on different genetic backgrounds, and in independent laboratories utilizing differing animal husbandry conditions. Furthermore, multiple other growth hormone signaling-deficient mouse mutants exhibiting longevity have since been reported.
Studies dating back a century have reported the healthspan and lifespan benefits of diets restricted in caloric content yet sufficient in macro- and micro-nutrients. These diets of "undernutrition without malnutrition" have been documented to have the ability to slow the progression of aging in multiple organ systems and in multiple species. Of particular note to this study, caloric restriction (CR) increases circulating GH levels in rats, dogs, and humans. To date, few reports have investigated the effects of this feeding paradigm on functional metrics of physical function.
The vast majority of studies on neuromusculoskeletal functioning in experimental gerontology deal with charting the prevalent, well-documented, aging-associated decline in neuromuscular or skeletal structure, strength, quality or performance. Save for studies with CR animals or on exercising animals, evidence of genetic or environmental factors that might improve physical functioning is limited; and, to the best of our knowledge, no combinatorial analysis of the interaction of two different factors has been conducted.
In this study, we conducted a longitudinal investigation of the individual and combined effects of Ames dwarfism or CR on measures of neuromusculoskeletal ability in senescing mice. Our initial hypothesis was that mice deficient in an anabolic process, such as GH signaling, would be inferior in performance on tasks requiring an integration of nervous, muscular, and skeletal systems' functions; as GH is crucial to the ontogeny and maintenance of those physiological systems. Thusly, we hypothesized that GH signaling-inhibiting Ames dwarfism will correlate with impaired function on late-life neuromusculoskeletal tasks, whereas GH signaling-enhancing CR will accentuate that performance. Our overall aim of revealing differences in physical capability between slow-aging mice and their normally aging counterparts was achieved for grip strength, balance, agility, and motor coordination; yet, some results ran counter to our hypotheses.
Our study objective was to determine whether Ames dwarfism or CR influence neuromusculoskeletal function in middle-aged (82 ± 12 weeks old) or old (128 ± 14 w.o.) mice. At the examined ages, strength was improved by dwarfism, CR, and dwarfism plus CR in male mice; balance/ motor coordination was improved by CR in old animals and in middle-aged females; and agility/ motor coordination was improved by a combination of dwarfism and CR in both genders of middle-aged mice and in old females. Therefore, extension of longevity by congenital hypopituitarism is associated with improved maintenance of the examined measures of strength, agility, and motor coordination, key elements of frailty during human aging, into advanced age.
From this longitudinal study, we report beneficial effects of either [dwarfism], caloric restriction, or both for physical functioning in aging mice. The individual effects of either factor, in combination with the additive effects seen during the motor coordination and agility testing, suggest that it is not merely a change in body composition (as CR reduces adiposity and Ames dwarfism increases it), difference in size (as CR mice are just as long as their ad-libitum-fed counterparts), or uniqueness of experimental design (as the three tests exerted considerably different challenges on the animals) that results in the benefits seen. Rather, we posit that the decrease in the rate of senescence induced by either factor is primarily responsible for the retention of neuromusculoskeletal function observed.
For many researchers the grail is to find ways to slow aging through medicine, to reproduce the reduction in the rate of senescence noted above. This will extend human life and push back the degenerative conditions of aging. It is also, unfortunately, a slow and expensive path forward that cannot ultimately produce therapies capable of rejuvenating the old - only therapies that slightly slow the pace at which the young become old. If these therapies only emerge when we are old, then it will be too late for us.
So this is not the path that the research community should take. Something different is needed for the decades of research that lie ahead, a research program more likely to result in actual rejuvenation of the old, and soon enough to matter.
CROWDFUNDING SUCCESS FOR MITOCHONDRIAL GENE THERAPY PROJECT
I'm pleased to note that the latest Longecity crowdfunding initiative has met its goal: $7,000 raised from the community and a further $14,000 provided by Longecity will go towards a mitochondrial gene therapy research project carried out by SENS Research Foundation staff. One of the wonders of our modern age is that meaningful life science research at the cutting edge is now so very cheap: things that would have required a fully staffed laboratory and tens of millions of dollars twenty years ago can be now be accomplished by a single researcher with $20,000 to spend. This new state of affairs is reflected in the pace of progress in medical research.
LongeCity Research Support 2013: Mitochondrial Gene Therapy
Mitochondria, the power plants of the cell, contain their own DNA. Unlike the nucleus, mitochondria lack an efficient system to repair damaged DNA, and this damage accumulates over time. As we age, these accumulated mutations result in an increase in oxidative stress throughout the body. It is no coincidence that organisms which age more slowly consistently display lower rates of mitochondrial free radical damage. Reversing and/or preventing damage to mitochondrial DNA may be a key factor in slowing the aging process. In this project, engineered mitochondrial genes will be used to restore function to cells that contain defective mitochondrial genes.
There is a good discussion of the research and its details going on in the project Q&A thread. You should take a look: this is the model for the future of a great deal of research funding, in which enthusiasts in the public fund the work they want to see accomplished, talking directly with the scientists who carry out this research. Openness, transparency, and continuous communication are powerful tools. The Longecity folk are justifiably pleased at another addition to their fundraising record:
Congratulations everyone. Once again LongeCity/Imminst has reached the fundraising goal of $7,000. This will now be matched with a $14,000 grant and the research can begin. In case you were not counting, our organization still has a 100% success rate of funding life extension research. Every fundraising goal for the last 5 years has been met or exceeded.
More of this will be welcome, and I expect to see more of this in the years ahead as the community grows, side by side with growth in traditional forms of funding for SENS and SENS-like rejuvenation research.
QUESTIONING TELOMERE DYNAMICS AS A PREDICTOR OF MORTALITY
Telomeres are caps of repeating DNA sequences at the end of chromosomes. They shorten with each cell division, a little lost when DNA is replicated, and are lengthened by the activity of the enzyme telomerase, which adds additional repeating sequences. When telomeres become very short cells cease to replicate or self-destruct. Thus average telomere length in the cells of any given tissue is a function of how frequently those cells replicate, local levels of telomerase activity, how frequently new cells with long telomeres are created by the stem cell population supporting that tissue, and most likely a range of other factors. Average telomere length tends to decline and the proportion of very short telomeres increase with stress, illness, and advancing age, the latter being effectively just another form of becoming ill.
Telomere length may or may not be an important contributing cause of aging. From where I stand it looks very much like a secondary marker of aging, a consequence of other forms of damage. But researchers have demonstrated extension of life in mice through use of telomerase to extend telomeres - so there is the possibility that in and of itself loss of telomere length is doing further harm.
Measuring telomere length is a business these days. A few young companies have launched to bring to the clinic the laboratory techniques developed for measuring telomere length in blood samples. The hope here is that this has some predictive or diagnostic value, and it certainly seems at first sight that something useful can be found in the data. But straightforward comparisons of telomere length and health do not tend to yield useful results, as illustrated by this and similar studies:
Longitudinal Changes in Leukocyte Telomere Length and Mortality in Humans
Leukocyte telomere length (LTL) ostensibly shortens with age and has been moderately associated with mortality. In humans, these findings have come almost solely from cross-sectional studies. Only recently has LTL shortening within individuals been analyzed in longitudinal studies. Such studies are relevant to establish LTL dynamics as biomarkers of mortality as well as to disentangle the causality of telomeres on aging.
We present a large longitudinal study on LTL and human mortality, where the 10-year change of LTL is analyzed in 1,356 individuals aged 30-70 years. We find age, smoking status, and alcohol consumption to be associated with LTL attrition and confirm a strong association with baseline LTL. The latter association might be an epiphenomenon of regression to the mean. We do not find an association of mortality with either absolute LTL or LTL attrition. This study establishes that certain lifestyle factors influence LTL dynamics. However, it questions the applicability of LTL dynamics as a predictor of mortality.
Other research groups have found that more complex measures, such as looking at the proportion of very short telomeres and changes in that metric over time, can produce better results in animal studies. So there may be ways to slice the data so as to produce a useful outcome.
ANOTHER SPOTLIGHT ON SENS RESEARCH FOUNDATION INTERNS
Each year the SENS Research Foundation (SRF) brings on a summer crew of young researchers, capable undergraduate and graduate life science students who perform original research to assist in building the foundations of future rejuvenation biotechnologies. This is a great opportunity for anyone interested in molecular biology and the potential for aging research to reshape itself into the largest and most important branch of medical science in the years ahead. These are the early days of the next big thing, and working with the SRF is a great way to build connections and show your worth in this field.
The Foundation staff have been posting a series on this year's interns and their thoughts on the recent SENS6 conference, and the latest few articles are up:
SRF Intern Brandon Frenz Models the Effect of Systemic Aging Factors
Aging is defined as the gradual loss of a tissue's functional stability, or homeostasis. Loss of tissue homeostasis ultimately results in tissue failure, disease, and the eventual death of the whole organism. Recent studies have shown that the rate of this decline is not an independent phenomenon but rather is regulated through systemic factors. For example, in one type of study known as heterochronic parabiosis, the circulatory systems of an old and young mouse are linked together. The reversal of several key indicators of age observed in the older mouse coupled with tissue homeostasis decline in the young mouse provides evidence that aging is regulated by systemic factors.
During my internship, I helped develop a model in the fruit fly Drosophila melanogaster to study systemically regulated aging. By creating DNA damage in a specific tissue in the fly (the primary tissue), I was able to study the effect it has on tissue elsewhere in the fly (the distal tissue). I also tested the system ex vivo (outside the fly) and was able to generate a stress response in the distal tissue when it was cultured in a media with the damaged primary tissue. The experiments I conducted during my internship indicate that our systemic aging model appears to be robust and functioning as intended. This model will now be used to determine precisely which systemic factors are driving the stress response observed in the distal tissue and ultimately better characterize how systemic signaling factors from an individual tissue can drive the rate of aging.
SRF Intern Brandon Frenz on SENS6
One presentation of particular note was given by Associate Professor of Chemistry at Yale Dr. David Spiegel. Dr. Spiegel's lab studies advanced glycation end products (AGEs). AGEs are by-products of aging that accumulate in the area between cells, called the extracellular matrix (ECM). AGEs have been implicated in a number of age-related diseases, including Alzheimer's Disease, cardiovascular disease, diabetes, and stroke. One major hurdle to develop technology to break down AGEs is obtaining sufficient chemically pure quantities for experimentation. During his presentation, Dr. Spiegel explained how his lab is chemically synthesizing AGEs, such as glucosepane, the most abundant AGE found in aged tissue, using thirteen-step synthetic sequence.
A new institute focused on protein design is being created at the University of Washington, where I am a biochemistry graduate student. I am particularly excited that synthetically designed AGE-breaker proteins easily could be tested and screened in vivo using Spiegel's breakthrough technology. I have begun talks with Dr. Spiegel about a potential collaboration and am hopeful that his synthesis protocol has provided the means to develop a method to clear glucosepane from the human body and thus alleviate some age-related diseases.
SENS6 Intern Research Award Winner Ethan Sarnoski Establishes a Link Between Senescence and Mitochondrial Dysfunction
Cellular senescence is invoked by normal dividing cells to prevent excessive cell growth. This protective mechanism prevents cells experiencing genomic stress, such as DNA damage, from becoming cancerous. However, senescent cells continue to persist and accumulate as we age. The secreted molecules from these accumulated senescent cells are hypothesized to contribute to chronic inflammation and overall aging of the organism.
Dr. Campisi's lab seeks to understand the cause of senescence as well as the effect senescence associated secreted proteins (SASPs) have on the aging process. One phenomenon associated with aging is an increased number of cells that exhibit mitochondrial dysfunction. Mitochondria are the cellular structures which convert our food into a form of cell energy known as ATP (or adenosine triphosphate) through a process called cellular respiration. ATP is produced during the final stage of cellular respiration, known as the electron transport chain. During a key step in the electron transport chain, the enzyme NADH (nicotinamide adenine dinucleotide) is oxidized into NAD+, an essential cofactor in an earlier step in cellular respiration known as glycolysis.
My research project sought to understand the role mitochondrial dysfunction can play in senescence and ultimately aging. I indeed observed that mitochondrial dysfunction is able to induce senescence in cultured cells. I also determined that the senescence response was triggered by depletion of NAD(P)+. This insight into the link between mitochondrial dysfunction and senescence is an important step in the development of interventions for preventing the accumulation of senescent cells and their adverse aging effects.
SRF Intern Ethan Sarnoski on SENS6
I'd like to tell you about one particularly engaging presentation: that of the founder and CEO of Immusoft Matthew Scholz's description of the current state of Immusoft's Immune System Programming (ISP) technology. [This] involves the genetic modification of specialized protein-secreting cells called plasmablasts. Plasmablasts are partially mature B lymphocytes with substantial but limited ability to proliferate. The Immusoft research team reprograms these cells, instructing them to secrete a therapeutic protein in addition to their normal products. Ultimately, the team hopes to translate this process to human medicine by collecting plasmablasts from a patient, modifying and expanding their numbers outside the body, and then reintroducing the modified plasmablasts as therapeutic protein factories. In other words, the Immusoft technology will program a patient's own immune cells to produce a therapeutic protein.
Preparations are currently underway for a clinical trial in collaboration with researchers at the University of California, San Francisco, where programmed plasmablasts will be used to secrete broadly neutralizing antibodies to HIV. These antibodies have been observed in HIV-resistant elite controllers, but have not been successfully elicited through conventional vaccine strategies. Production of these antibodies with ISP cells represents a promising prophylactic measure for the prevention of HIV. Further studies may allow Immusoft's ISP technology to address such issues as age-related degeneration, optimization of blood cholesterol levels, and multiple rare diseases.
PROSPECTS FOR REGENERATION OF ORGANS WITHOUT STEM CELLS
Biology is enormously complex, and it should never really be a surprise to find that different parts of the body have evolved different methodologies for achieving the same goal - such as tissue maintenance, to pick one example. So while it seems to be the case that small populations of stem cells support most or all of our tissues, offering the opportunity for researchers to build therapies based on enhancing the activities or increasing the numbers of these stem cells, there may be some exceptions to this rule. There may also be separate and distinct methods of tissue maintenance that operate in parallel to one another, and until they have been discovered and cataloged who can say whether one might be easier to manipulate than the others? At this point all could be candidates for regenerative therapies.
In this context, here is an interesting report on recent research into kidney regeneration, which strongly suggests that stem cells are not the agent at work here:
A new model for organ repair
Harvard Stem Cell Institute (HSCI) researchers have a new model for how the kidney repairs itself, a model that adds to a growing body of evidence that mature cells are far more plastic than had previously been imagined. After injury, mature kidney cells dedifferentiate into more primordial versions of themselves, and then differentiate into the cell types needing replacement in the damaged tissue. This finding conflicts with a previously held theory that the kidney has scattered stem cell populations that respond to injury.
Benjamin Humphreys [was] suspicious of the kidney stem cell repair model because his previous work suggested that all kidney cells have the capacity to divide after injury. He and his colleagues decided to test conventional wisdom by genetically tagging mature kidney cells in mice that do not express stem cell markers; the hypothesis being that the mature cells should do nothing or die after injury. The results showed that not only do these fully differentiated cells multiply, but they can multiply several times as they help to repair the kidney. This new interpretation of kidney repair suggests a model by which cells reprogram themselves; similar to the way mature cells can be chemically manipulated to revert to an induced pluripotent state.
"One has to remember that not every organ necessarily is endowed with clear and well-defined stem cell populations, like the intestines or the skin. I'm not saying that kidney stem cells don't exist, but in tissues where cell division is very slow during homeostasis, there may not have been an evolutionary pressure for stem cell mechanisms of repair." He plans to apply his kidney repair discovery to define new therapeutic targets in acute kidney injury. The goal would be to find drugs that accelerate the process of dedifferentiation and proliferation of mature kidney cells in response to injury, as well as slow down pathways that impair healing or lead to scar tissue formation.
Below is a link to the paper, which is unfortunately not open access:
Differentiated kidney epithelial cells repair injured proximal tubule
When epithelial cells in the proximal portion of the nephron are damaged they rapidly proliferate to repair the damage to the kidney. Whether a stem cell is responsible for this proliferative response or not is controversial. Although a scattered population of cells can be found in the human proximal tubule that seem to have stem-cell characteristics, they could also represent isolated damaged cells that have dedifferentiated and lost their epithelial characteristics. We resolve these conflicting models using genetic lineage analysis to demonstrate that fully differentiated proximal tubule cells not only proliferate after injury, but they also upregulate apparent stem-cell markers. This study shows that epithelial dedifferentiation is responsible for repair of mouse proximal tubule, rather than an adult stem-cell population.
LATEST HEADLINES FROM FIGHT AGING!
WORK ON A CYTOMEGALOVIRUS VACCINE
Monday, October 28, 2013
Much of the age-related decline of the immune system can be blamed on cytomegalovirus (CMV). Near everyone is exposed to this type of herpesvirus at some point in life, and because the immune system cannot effectively clear it from the body ever more immune cells become uselessly and redundantly specialized to attack it. Since the immune system is limited in the number of cells it can support at any given time, this means that there are ever fewer cells capable of responding effectively to new threats, or patrolling the body to destroy senescent or cancerous cells.
An effective cytomegalovirus vaccine or other method of clearance and prevention will be useful for the young, and research is progressing, but this isn't an effective treatment for the old. There, the damage is already done. The best approach for rejuvenation of the immune system in this case is something along the lines of introducing new cells and destroying existing CMV-specialized cells to free up space. Nonetheless, here is an example of progress towards an effective vaccine for CMV:
Identification of immune correlates of protection for viral vaccines is complicated by multiple factors, but there is general consensus on the importance of antibodies that neutralize viral attachment to susceptible cells. Development of new viral vaccines has mostly followed this neutralizing antibody paradigm, but as a recent clinical trial of human cytomegalovirus (HCMV) vaccination demonstrated, this singular approach can yield limited protective efficacy.
Since HCMV devotes more than 50% of its coding capacity to proteins that modulate host immunity, it is hypothesized that expansion of vaccine targets to include this part of the viral proteome will disrupt viral natural history. HCMV and rhesus cytomegalovirus (RhCMV) each encode an ortholog to the cellular interleukin-10 (cIL-10) cytokine: cmvIL-10 and rhcmvIL10, respectively. Despite extensive sequence divergence from their host's cIL-10, each viral IL-10 retains nearly identical functionality to cIL-10.
Uninfected rhesus macaques were immunized with engineered, nonfunctional rhcmvIL-10 variants, which were constructed by site-directed mutagenesis to abolish binding to the cIL-10 receptor. Vaccinees developed antibodies that neutralized rhcmvIL-10 function with no cross-neutralization of cIL-10. Following subcutaneous RhCMV challenge, the vaccinees exhibited both reduced RhCMV replication locally at the inoculation site and systemically and significantly reduced RhCMV shedding in bodily fluids compared to controls. Attenuation of RhCMV infection by rhcmvIL-10 vaccination argues that neutralization of viral immunomodulation may be a new vaccine paradigm for HCMV by expanding potential vaccine targets.
ONGOING WORK ON AN ALZHEIMER'S VACCINE
Monday, October 28, 2013
Several different lines of work aim at directing the immune system to remove proteins involved in causing Alzheimer's disease pathology. This is one example:
Since the first case of Alzheimer's was described, the disease has been associated with the presence of insoluble deposits called amyloid plaques. However, in the past decade researchers have been able to conclude that the neuronal death characteristic of the disease is not due to the presence of these plaques but to the toxicity of the soluble aggregates preceding them (and called oligomers).
Immunotherapy, consisting of the use of antibodies as a treatment for the disease, is turning out to be a encouraging tool in the treatment of certain types of cancer and has also been used in trials to treat Alzheimer's disease. Nevertheless, the clinical trial which had advanced most in treating Alzheimer's through passive vaccination - using the bapineuzumab antibody - was halted in 2012 during its last trial phase due to the adverse effects of the treatment. Many scientists believe the effects were the result of administering complete antibodies, which produce inflammation in the brain. For this reason, they propose to administer antibody fragments, which has been seen to be much safer.
The research group [thus] designed a recombinant antibody fragment (called scFv-h3D6: single-chain variable Fragment), a derivative of bapineuzumab, which only contains the active part that fights against the etiological agent of the disease: the domains of the antibody responsible for the union of Aβ oligomers. Scientists observed how, in human cell cultures, this antibody fragment protects from cell death and described the molecular mechanism by which this antibody fragment removes the Aβ oligomers that cause the disease.
Mice models of Alzheimer's have been treated successfully with [the] antibody fragment. One abdominal injection and only five days later the animals improved their memory and ability to learn as the result of less aggregated toxins and an increase in the number of neurons. At [the] molecular level, researchers demonstrated two important facts: first, the new treatment eliminates from the cerebral cortex [the] oligomers, the elements causing the disease; and second, that this elimination is linked to the recovery in levels of certain apolipoproteins which are suspected to be the natural eliminators of Aβ peptide aggregations.
INTRAMUSCULAR FAT AS A CONTRIBUTING CAUSE OF SARCOPENIA
Tuesday, October 29, 2013
Sarcopenia is the characteristic loss of muscle mass and strength that occurs with aging. Among the suspected root causes are lack of exercise, failing blood vessel function, increasing levels of inflammation due to immune system aging and fat tissue, and changes in the ability of the body to process leucine from the diet. Interestingly the practice of calorie restriction is shown to mitigate the progress of sarcopenia, which might be taken as another vote for fat-related and inflammation-related causes, as calorie restricted individuals are lean and excess visceral fat tissue contributes considerably to levels of chronic inflammation.
Human aging is associated with a progressive loss of muscle mass and strength and a concomitant fat accumulation in form of inter-muscular adipose tissue, causing skeletal muscle function decline and immobilization. Fat accumulation can also occur as intra-muscular triglycerides (IMTG) deposition in lipid droplets, which are associated with perilipin proteins, such as Perilipin2 (Plin2). It is not known whether Plin2 expression changes with age and if this has consequences on muscle mass and strength.
We studied the expression of Plin2 in the vastus lateralis (VL) muscle of both healthy subjects and patients affected by lower limb mobility limitation of different age. We found that Plin2 expression increases with age, this phenomenon being particularly evident in patients. Moreover, Plin2 expression is inversely correlated with quadriceps strength and VL thickness. To investigate the molecular mechanisms underpinning this phenomenon, we focused on IGF-1/p53 network/signalling pathway, involved in muscle physiology. We found that Plin2 expression strongly correlates with increased p53 activation and reduced IGF-1 expression.
To confirm these observations made on humans, we studied mice overexpressing muscle-specific IGF-1, which are protected from sarcopenia. These mice resulted almost negative for the expression of Plin2 and p53 at two years of age. We conclude that fat deposition within skeletal muscle in form of Plin2-coated lipid droplets increases with age and is associated with decreased muscle strength and thickness, likely through an IGF-1- and p53-dependent mechanism. The data also suggest that excessive intramuscular fat accumulation could be the initial trigger for p53 activation and consequent loss of muscle mass and strength.
PROPOSING THE CROSS-LINK EGGL AS A TARGET IN AGING TISSUE
Tuesday, October 29, 2013
Between our cells is the complex support structure of the extracellular matrix. It becomes extensively damaged in aging by the formation of cross-linked proteins, stuck together by sugars and other metabolic byproducts that the body fails to clear. This causes loss of elasticity in tissues like skin and blood vessels, as well as numerous other forms of harm. Glucosepane is by far the most important of these cross-linking compounds, but there is comparatively little work being done on ways to break down glucosepane, and thus reverse its effects on tissues, and remove this contribution to degenerative aging.
Here one of the researchers involved in present work on clearing glucosepane advances another target cross-link compound that might also be addressed:
Ageing of the extracellular matrix (ECM), the protein matrix that surrounds and penetrates the tissues and binds the body together, contributes significantly to functional aging of tissues. ECM proteins become increasingly cross-linked with age, and this cross-linking is probably important in the decline of the ECM's function. In this paper I review the role of EGGL, a cross-link formed by transglutaminase enzymes, and particularly the widely expressed isozyme TG2, in the aging ECM.
There is little direct data on EGGL accumulation with age, and no direct evidence of a role of EGGL in the aging of the ECM outwith pathology. However, several lines of circumstantial evidence suggest that EGGL accumulates with age, and its association with pathology suggests that this might reflect degradation of ECM function. TG activity increases with age in many circumstances, ECM protein turnover is such that some EGGL made by TG is likely to remain in place for years if not decades in healthy tissue, and both EGGL and TG levels are enhanced by age-related diseases.
If further research shows EGGL does accumulate with age, removing it could be of therapeutic benefit. I review blockade of TG and active removal of EGGL as therapeutic strategies, and conclude that both have promise. EGGL removal may have benefit for acute fibrotic diseases such as tendinopathy, and for treating generalized decline in ECM function with old age. Extracellular TG2 and EGGL are therefore therapeutic targets both for specific and more generalized diseases of aging.
APOLIPOPROTEIN D EXPRESSION CORRELATES WITH REDUCED AGE-RELATED NEURODEGENERATION
Wednesday, October 30, 2013
Here is an example of the sort of correlations that emerge on a regular basis from human studies of degenerative aging and variations in genes and gene expression:
The lipocalin apolipoprotein D (Apo D) is upregulated in peripheral nerves following injury and in regions of the central nervous system, such as the cerebral cortex, hippocampus, and cerebellum, during aging and progression of certain neurological diseases.
In contrast, few studies have examined Apo D expression in the brainstem, a region necessary for survival and generally less prone to age-related degeneration. We measured Apo D expression in whole human brainstem lysates by slot-blot and at higher spatial resolution by quantitative immunohistochemistry. In contrast to cortex, hippocampus, and cerebellum, apolipoprotein D was highly expressed in brainstem tissue from subject with no history of neurological disease, and expression showed little variation with age. Both neurons and glia expressed Apo D, particularly neurons with larger somata and glia in the periphery of these brainstem centers. We propose that strong brainstem expression of Apo D throughout adult life contributes to resistance against neurodegenerative disease and age-related degeneration, possibly by preventing oxidative stress and ensuing lipid peroxidation.
EXAMINING THE EPIGENETIC EFFECTS OF EXERCISE
Wednesday, October 30, 2013
Epigenetics is the study of how genetic blueprints are turned into proteins, a process called gene expression, and how this process is regulated to create dynamic variations in levels of protein production. Protein production shifts in response to diet, environment, aging, and other factors, and can have a large impact on long-term health. The practice of calorie restriction produces sweeping epigenetic changes for example, leading to significantly longer healthy lives in laboratory animals.
Here researchers review work on the epigenetics of exercise in humans. Cataloging epigenetic alterations that occur in response to exercise is an early step on the road to trying to reproduce these changes using drugs or other techniques. At some point it will be possible for all of us to have optimal operation of metabolism for long-term health without actually undertaking exercise or calorie restriction or having good genes. But it is worth considering that this outcome is still a long way distant, and the old-fashioned methods of achieving the same goals are free, proven, and presently available to everyone.
Most human phenotypes are influenced by a combination of genomic and environmental factors. Engaging in regular physical exercise prevents many chronic diseases, decreases mortality risk and increases longevity. However, the mechanisms involved are poorly understood. The modulating effect of physical (aerobic and resistance) exercise on gene expression has been known for some time now and has provided us with an understanding of the biological responses to physical exercise.
Emerging research data suggest that epigenetic modifications are extremely important for both development and disease in humans. In the current review, we summarise findings on the effect of exercise on epigenetic modifications and their effects on gene expression. Current research data suggest epigenetic modifications (DNA methylation and histone acetylation) and microRNAs (miRNAs) are responsive to acute aerobic and resistance exercise in brain, blood, skeletal and cardiac muscle, adipose tissue and even buccal cells. Six months of aerobic exercise alters whole-genome DNA methylation in skeletal muscle and adipose tissue and directly influences lipogenesis. Some miRNAs are related to maximal oxygen consumption (VO2max) and VO2max trainability, and are differentially expressed amongst individuals with high and low VO2max.
Remarkably, miRNA expression profiles discriminate between low and high responders to resistance exercise (miR-378, -26a, -29a and -451) and correlate to gains in lean body mass (miR-378). The emerging field of exercise epigenomics is expected to prosper and additional studies may elucidate the clinical relevance of miRNAs and epigenetic modifications, and delineate mechanisms by which exercise confers a healthier phenotype and improves performance.
REACTIVING DORMANT STEM CELLS IN THE AGING HEART
Thursday, October 31, 2013
Stem cell populations decline in activity and possibly size with aging. This is most likely an evolved response to rising levels of damage that works to reduce cancer risk but causes increasing frailty and degeneration of tissue function. The exact mechanisms are probably different in different cell types and organs, but researchers have been making some progress in uncovering ways to trigger various types of stem cells to return to work. This can produce considerable benefits in terms of improved regeneration and tissue maintenance, but is probably going to come with an associated raised risk of cancer. For best effect we want researchers to work on removing the underlying damage that causes stem cells to go silent, rather than try to boost the activity of a damaged engine.
Here is an example of recent research of this type, in which a way to revive some of the heart's stem cells is found, and the proximate cause of their quiescence identified:
Hypoxia favors stem cell quiescence, while normoxia is required for their activation; but whether cardiac stem cell (CSC) function is regulated by the hypoxic/normoxic state of the cell is currently unknown. A balance between hypoxic and normoxic CSCs may be present in the young heart, although this homeostatic control may be disrupted with aging. Defects in tissue oxygenation occur in the old myocardium, and this phenomenon may expand the pool of hypoxic CSCs, which are no longer involved in myocyte renewal.
Here we show that the senescent heart is characterized by an increased number of quiescent CSCs with intact telomeres that cannot reenter the cell cycle and form a differentiated progeny. Conversely, myocyte replacement is controlled only by frequently dividing CSCs with shortened telomeres; these CSCs generate a myocyte population that is chronologically young but phenotypically old. Telomere dysfunction dictates their actual age and mechanical behavior. However, the residual subset of quiescent young CSCs can be stimulated in situ by stem cell factor reversing the aging myopathy.
Our findings support the notion that strategies targeting CSC activation and growth interfere with the manifestations of myocardial aging in an animal model. Although caution has to be exercised in the translation of animal studies to human beings, our data strongly suggests that a pool of functionally-competent CSCs persists in the senescent heart and this stem cell compartment can promote myocyte regeneration effectively, correcting partly the aging myopathy.
EVALUATING EXERCISE AND HEALTH IS HARDER THAN YOU MIGHT THINK
Thursday, October 31, 2013
Studies of exercise show that moderate regular exercise produces meaningful benefits in health and longevity. Life expectancy is improved by five years, give or take, incidence of age-related disease is lower, and lifetime medical costs are lower. The challenge here when trying to put numbers to the benefits of exercise is that day to day activity for many people rises to the level of moderate regular exercise. Quantifying this activity can be hard, however, and may greatly increase the cost of a study. Even in the old, activities that wouldn't ordinarily be counted as deliberate exercise have an impact on health. This has only become very clear in recent years, with the emergence of small, widely available accelerometers that study participants can wear throughout the day.
Here, for example, is a study to show that non-exercise activity does is correlated with health and longevity, as you might expect:
Sedentary time is increasing in all societies and results in limited non-exercise physical activity (NEPA) of daily life. The importance of low NEPA for cardiovascular health and longevity is limited, especially in elderly. [This study examines] the association between NEPA and cardiovascular health at baseline as well as the risk of a first cardiovascular disease (CVD) event and total mortality after 12.5 years. Every third 60-year-old man and woman in Stockholm County was invited to a health screening study; 4232 individuals participated (78% response rate). At baseline, NEPA and exercise habits were assessed from a self-administrated questionnaire and cardiovascular health was established through physical examinations and laboratory tests. The participants were followed for an average of 12.5 years for the assessment of CVD events and mortality.
At baseline, high NEPA was, regardless of regular exercise and compared with low NEPA, associated with more preferable waist circumference, high-density lipoprotein cholesterol and triglycerides in both sexes and with lower insulin, glucose and fibrinogen levels in men. Moreover, the occurrence of the metabolic syndrome was significantly lower in those with higher NEPA levels in non-exercising and regularly exercising individuals. Furthermore, reporting a high NEPA level, compared with low, was associated with a lower risk of a first CVD event (hazard ratio of 0.73) and lower all-cause mortality (hazard ratio of 0.70). A generally active daily life was, regardless of exercising regularly or not, associated with cardiovascular health and longevity in older adults.
GHRH KNOCKOUT MICE LIVE 50% LONGER, AND LONGER STILL WITH CALORIE RESTRICTION
Friday, November 1, 2013
Removing growth hormone or blocking its activities tends to makes mice live longer. The record for longest-lived genetically engineered mice is held by those in which growth hormone receptor is eliminated, for example. Here is an example of another methodology:
There is increasing evidence that the hormonal systems involved in growth, the metabolism of glucose, and the processes that balance energy intake and expenditure might also be involved in the aging process. In rodents, mutations in genes involved in these hormone-signaling pathways can substantially increase lifespan, as can a diet that is low in calories but which avoids malnutrition. As well as living longer, such mice also show reductions in age-related conditions such as diabetes, memory loss and cancer.
Many of these effects appear to involve the actions of growth hormone. Mice with mutations that disrupt the development of the pituitary gland, which produces growth hormone, show increased longevity, as do mice that lack the receptor for growth hormone. However, these animals also show changes in a number of other hormones, making it difficult to be sure that the reduction in growth hormone signaling is responsible for their increased lifespan.
[Researchers] have now studied mutant mice that lack a gene called GHRH, which promotes the release of growth hormone. These mice, which have normal levels of all other pituitary hormones, lived for up to 50% longer than their wild-type littermates. They were more active than normal mice and had more body fat, and showed greatly increased sensitivity to insulin.
Some of the changes in these mutant mice resembled those seen in animals with a restricted calorie intake, suggesting that the same mechanisms may be implicated in both. [However], caloric restriction further increased the lifespans [of] GHRH knockout mice, indicating that at least some of the effects of caloric restriction are independent of disrupted growth hormone signaling.
HARDENING OF ARTERIES LINKED TO PLAQUES IN BRAIN
Friday, November 1, 2013
One of the challenges inherent in identifying meaningful associations in aging is that degeneration is a global phenomenon: every tissue accumulates damage and becomes increasingly dysfunctional. It may be that for any two features of aging you care to compare, the only underlying link is that damage occurs. People with more damage have more dysfunction in both areas, people with less damage have less dysfunction in both areas. It isn't necessarily the case that these two features have any direct interaction with one another at all. It's worth bearing this in mind when reading the results of correlation studies in aging, as there has to be a much better argument than just the fact of correlation to establish a link of causation:
Even for elderly people with no signs of dementia, those with hardening of the arteries are more likely to also have the beta-amyloid plaques in the brain that are a hallmark of Alzheimer's disease. "This is more evidence that cardiovascular health leads to a healthy brain."
The study involved 91 people with an average age of 87 who did not have dementia. Researchers took scans of the participants' brains to measure any plaques in the brain. The amount of stiffness in the participants' arteries was measured about two years later. Half of all participants had beta-amyloid plaques. People with beta-amyloid plaques were more likely to have high systolic blood pressure, higher average blood pressure and higher arterial stiffness as measured with the brachial-ankle method. For every unit increase inbrachial-ankle arterial stiffness, people were twice as likely to have beta-amyloid plaques in the brain.
Arterial stiffness was highest in people who had both amyloid plaques and white matter hyperintensities in the brain, or brain lesions. "These two conditions may be a 'double-hit' that contributes to the development of dementia. Compared to people who had low amounts of amyloid plaques and brain lesions, each unit of increase in arterial stiffness was associated with a two- to four-fold increase in the odds of having both amyloid plaques and a high amount of brain lesions. This study adds to growing evidence that hardening of the arteries is associated with cerebrovascular disease that does not show symptoms. Now we can add Alzheimer's type lesions to the list."