Posts tagged aging
Articles and news from the latest research reports.
Neuroscientists show ’jumping genes’ may contribute to aging-related brain defects
As the body ages, the physical effects are notable; wrinkles in the skin appear, physical exertion becomes harder. But there are also less visible processes going on. Inside aging brains there is another phenomenon at work, which may contribute to age-related brain defects.
In a paper published in the journal Nature Neuroscience CSHL Associate Professor Joshua Dubnau and colleagues show that so-called “jumping genes,” or transposons, increase in abundance and activity in the brains of fruit flies as they age.
Originally discovered at CSHL by Professor Barbara McClintock while working on maize (corn) in the 1940s, transposons are typically repeat DNA sequences that insert themselves into the DNA of an animal or plant.
The moniker “jumping genes” comes from the fact that when activated they can reinsert themselves, or transpose, into another part of the genome. In the course of doing so they are thought to either provide variations in genetic function or, especially in the germline, induce potentially fatal disruptive defects.
Jumping genes in the brains of fruit flies
The median lifespan of a fruit fly can be measured in days. The average fly lives for somewhere between 40-50 days. But they provide a powerful model with which to get at the genetics of things like aging and brain function, including memory.
Dubnau’s interest was piqued by an experiment in which his team showed that when the activity of a protein called Ago2 (Argonaute 2) was perturbed, so was long-term memory—which was tested using a trained Pavolvian response to smell. “This is a neurodegenerative defect that gets profoundly more apparent with age of the flies,” notes Dubnau.
Since Ago2 is known to be involved in protecting against transposon activity in fruit flies, Dubnau and colleagues in his lab, including Wanhe Li and Lisa Prazak, were compelled to look for transposons.
Though transposons have been shown to be active during normal brain development, they are silenced soon afterward. The implication is that they have some functional role in development.
When Dubnau’s group looked for transposons they found that there is a marked increase in transposon levels in the brain cells, or neurons, by 21 days of age in normal fruit flies. The levels were observed to increase steadily with age. These transposons, including one in particular called gypsy, were highly active, jumping from place to place in the genome.
When they blocked Ago2 from being expressed in fruit flies, transposons accumulated at a much younger age. In fact the levels of transposons in young Ago2 “knock-out” flies were equivalent to those in much older normal flies, and increased further still as the Ago2 knock-out flies aged.
Accompanying this transposon accumulation were defects in long-term memory that mirrored those usually seen in much older flies, as well as a much-reduced lifespan. “Essentially the Ago2 knock out flies have no long-term memory by the time they are 20 days old, while normal flies have a normal long-term memory at the same age,” Dubnau reports.
In a previous paper the Dubnau lab, in collaboration with CSHL Assistant Professor Molly Hammell, established a connection between transposons and devastating neurodegenerative diseases such ALS (amyotrophic lateral sclerosis, or Lou Gehrig’s disease) and FTLD (frontotemporal lobar degeneration). The link was the protein TDP-43, which they showed controls transposon activity.
Taken together with the results in his team’s new paper, Dubnau proposes that a “transposon storm” may be responsible for age-related neurodegeneration as well as the pathology seen in some neurodegenerative disorders.
However, his studies so far don’t address whether transposons are the cause or an effect of aging-related brain defects. “The next step will be to activate transposons by genetically manipulating fruit flies and ask whether they are a direct cause of neurodegeneration,” Dubnau says.
Motor skills research nets good news for middle-aged
People in their 20s don’t have much on their middle-aged counterparts when it comes to some fine motor movements, researchers from UT Arlington have found.
In a simple finger-tapping exercise, study participants’ speed declined only slightly with age until a marked drop in ability with participants in their mid-60s.
Priscila Caçola, an assistant professor of kinesiology at The University of Texas at Arlington, hopes the new work will help clinicians identify abnormal loss of function in their patients. Though motor ability in older adults has been studied widely, not a lot of research has focused on when deficits begin, she said.
The journal Brain and Cognition will include the study in its June 2013 issue. It is already available online.
“We have this so-called age decline, everybody knows that. I wanted to see if that was a gradual process,” Caçola said. “It’s good news really because I didn’t see differences between the young and middle-aged people.”
Caçola’s co-authors on the paper are Jerroed Roberson, a senior kinesiology major at UT Arlington, and Carl Gabbard, a professor in the Texas A&M University Department of Health and Kinesiology.
The researchers based their work on the idea that before movements are made, the brain makes a mental plan. They used an evaluation process called chronometry that compares the time of test participants’ imagined movements to actual movements. Study participants – 99 people ranging in age from 18 to 93 – were asked to imagine and perform a series of increasingly difficult, ordered finger movements. They were divided into three age groups – 18-32, 40-63 and 65-93 – and the results were analyzed.
“What we found is that there is a significant drop-off after the age of 64,” Roberson said. “So if you see a drop-off in ability before that, then it could be a signal that there might be something wrong with that person and they might need further evaluation.”
The researchers also noted that the speed of imagined movements and executed actions tended to be closely associated within each group. That also could be useful knowledge for clinicians, the study said.
“The important message here is that clinicians should be aware that healthy older adults are slower than younger adults, but are able to create relatively accurate internal models for action,” the study said.
Caçola is a member of UT Arlington Center for Health Living and Longevity. She has published previous research on the links between movement representation and motor ability in children.
Separate lives: Neuronal and organismal lifespans decoupled
Replicative aging (also known as replicative senescence) causes mammalian cells to undergo a process of growth arrest dependent on telomeres (the shortening of repeated sequences at the ends of chromosomes). Neurons, on the other hand, are exempt from aging, and so the question of their actual lifespan has remained unanswered. Recently, however, scientists at the University of Pavia and the University of Turin demonstrated that neuronal lifespan is not limited by the organism’s maximum lifespan but, remarkably, continues when transplanted in a longer-living host. The researchers accomplished this by transplanting embryonic mouse cerebellar precursors into the developing brain of longer-living rats, in which the grafted mouse neurons survived for up to three years – twice the average lifespan of the donor mice.
Dr. Lorenzo Magrassi discussed the challenges he and his colleagues, Dr. Ketty Leto and Dr. Ferdinando Rossi, encountered in their research. “Cell transplantation into the developing rat brain is a technique that was originally developed by us and other research groups in the early nineties of the last century,” Magrassi tells Medical Xpress. “In recent years, we improved the protocol that, now standardized, allows reliable implantation rates with good survival rates.” While not all implanted embryos develop into adult animals carrying a viable transplant, Magrassi adds, the percentage of those that do is sufficient to plan a long-term survival experiment involving roughly 100 such successfully-born animals.
In addressing these challenges, Magrassi says that together with the intrinsic bonus of studying cells inside the nervous system, which is immunoprivileged, they transplanted cells before development of the thymus (a specialized organ of the immune system) was complete. The latter can help induce immunological tolerance in the host to the engrafted cells.
One remaining question is if their research can potentially be extended to determine whether or not a maximum lifespan exists for any postmitotic mammalian cells – Including neurons. “Similar techniques can, in principle, be extended to other organs containing perennial cells,” Magrassi notes, “but we don’t have direct experience with injecting cells into organs outside of the central nervous system.” Since the central nervous system is privileged compared to other organs that are more prone to immunological surveillance and attack, a major problem when transferring their experimental paradigm to other organs, he explains, could be an increase in immunological problems.
The scientists say their results suggest that neuronal survival and aging are coincidental but separable processes, thus increasing the hope that extending organismal lifespan by dietary, behavioral, and pharmacologic interventions will not necessarily result in a neuronally depleted brain. “Even after taking into account the obvious species differences, our results in rodents can be extrapolated by analogy to humans and other longer-living species where this sort of experiment is impossible,” Magrassi explains. “Our findings suggest that extending life by extending average organismal lifespan – a hallmark of all technologically advanced societies – will not necessarily result in neuron-impoverished brains well before the longer-living individual dies.” This bodes well for those studying life extension: Their efforts are not intrinsically futile, Magrassi notes, because in the absence of pathology, prolonging life span does not necessarily mean dementia due to widespread loss of neurons, as many people still think. “Roughly speaking,” Magrassi illustrates, “if the average lifespan of humans is now 80 years, our results suggest that at ages up to 160 years our neurons can survive if not hit by specific insults.
That said, however, Magrassi acknowledges that neuronal death is not the only effect of normal aging in the brain. “For example,” he illustrates, “cerebellar neurons – which in term of synaptic loss behave like the majority of neurons in the brain – show a substantial loss of dendritic branches, spines and synapses in normal aging. In our research, we studied transplanted mouse Purkinje cells to determine if their spine density decreased with time at the same rate of Purkinje cells in the mouse or in the rat.” Purkinje cells are large GABAergic (that is, gamma-Aminobutyric acid-producing) neurons, with many branching extensions, found in the cortex of the cerebellum. “The results of our experiments indicate that age-related progressive spine loss of grafted mouse Purkinje cells follows a slower pace, typical of the longer living rat, thus reaching absolute levels of spine loss comparable to those observed in aged mice at much longer survival times that are typical of the rat.”
Moreover, Magrassi adds that their experiments clearly show that by escaping immunological rejection, transplanted neurons can survive undisturbed for the entire life of the host. “This has implications for the ongoing discussion of the detrimental effects of immune attacks on transplanted neural cells for therapeutic purposes,”
Moving forward, in order to screen for intra- and extracellular changes that could be responsible for the long term survival of the mouse cells transplanted into rat brains – as well as the slowdown of dendritic spine loss – the team is planning to perform host and transplanted cell microdissection followed by a proteomic approach. “If we discover what factor or factors cause those changes,” Magrassi points out, “we could hopefully then develop more efficient drugs for treating all pathological neurodegenerative conditions in which neurons start to lose synaptic contacts and die well before organismal death – for example, dementia, memory loss and cognitive impairment. Of course,” he adds, “this work is still in progress and the results are preliminary.”
In addition, the scientists are currently testing xenotransplantation using different transgenic mouse strains with altered aging pathways as donors to characterize the pathways that led to their results.
Magrassi sees other areas of research that might benefit from their study. “Knowing that neuronal aging in rodents is not a cell-autonomous process is important not only for neuroscience,” he concludes. “It also has implications for evolutionary biology and epidemiology.”
(Source: medicalxpress.com)
Parkinsons’ drug helps older people to make decisions
A drug widely used to treat Parkinson’s Disease can help to reverse age-related impairments in decision making in some older people, a study from researchers at the Wellcome Trust Centre for Neuroimaging has shown.
The study, published today in the journal Nature Neuroscience, also describes changes in the patterns of brain activity of adults in their seventies that help to explain why they are worse at making decisions than younger people.
Poorer decision-making is a natural part of the ageing process that stems from a decline in our brains’ ability to learn from our experiences. Part of the decision-making process involves learning to predict the likelihood of getting a reward from the choices that we make.
An area of the brain called the nucleus accumbens is responsible for interpreting the difference between the reward that we’re expecting to get from a decision and the reward that is actually received. These so called ‘prediction errors’, reported by a brain chemical called dopamine, help us to learn from our actions and modify our behaviour to make better choices the next time.
Dr Rumana Chowdhury, who led the study at the Wellcome Trust Centre for Neuroimaging at UCL, said: “We know that dopamine decline is part of the normal aging process so we wanted to see whether it had any effect on reward-based decision making. We found that when we treated older people who were particularly bad at making decisions with a drug that increases dopamine in the brain, their ability to learn from rewards improved to a level comparable to somebody in their twenties and enabled them to make better decisions.”
The team used a combination of behavioural testing and brain imaging techniques, to investigate the decision-making process in 32 healthy volunteers aged in their early seventies compared with 22 volunteers in their mid-twenties. Older participants were tested on and off L-DOPA, a drug that increases levels of dopamine in the brain. L-DOPA, more commonly known as Levodopa, is widely used in the clinic to treat Parkinson’s.
The participants were asked to complete a behavioural learning task called the two-arm bandit, which mimics the decisions that gamblers make while playing slot machines. Players were shown two images and had to choose the one that they thought would give them the biggest reward. Their performance before and after drug treatment was assessed by the amount of money they won in the task.
"The older volunteers who were less able to predict the likelihood of a reward from their decisions, and so performed worst in the task, showed a significant improvement following drug treatment," Dr Chowdhury explains.
The team then looked at brain activity in the participants as they played the game using functional Magnetic Resonance Imaging (fMRI), and measured connections between areas of the brain that are involved in reward prediction using a technique called Diffusor Tensor Imaging (DTI).
The findings reveal that the older adults who performed best in the gambling game before drug treatment had greater integrity of their dopamine pathways. Older adults who performed poorly before drug treatment were not able to adequately signal reward expectation in the brain – this was corrected by L-DOPA and their performance improved on the drug.
Dr John Williams, Head of Neuroscience and Mental Health at the Wellcome Trust, said: “This careful investigation into the subtle cognitive changes that take place as we age offers important insights into what may happen at both a functional and anatomical level in older people who have problems with making decisions. That the team were able to reverse these changes by manipulating dopamine levels offers the hope of therapeutic approaches that could allow older people to function more effectively in the wider community.”
(Source: eurekalert.org)
Dynamic new software improves care of aging brain
Innovative medical records software developed by geriatricians and informaticians from the Regenstrief Institute and the Indiana University Center for Aging Research will provide more personalized health care for older adult patients, a population at significant risk for mental health decline and disorders.
A new study published in eGEMs, a peer-reviewed online publication recently launched by the Electronic Data Methods Forum, unveils the enhanced Electronic Medical Record Aging Brain Care Software, an automated decision-support system that enables care coordinators to track the health of the aging brain and help meet the complex biopsychosocial needs of patients and their informal caregivers.
The eMR-ABC captures and monitors the cognitive, functional, behavioral and psychological symptoms of older adults suffering from dementia or depression. It also collects information on the burden placed on patients’ family caregivers.
Utilizing this information, the software application provides decision support to care coordinators, who, working with physicians, social workers and other members of the health care team, create a personalized care plan that includes evidence-based non-pharmacological protocols, self-management handouts and alerts of medications with potentially adverse cognitive effects. The software’s built-in engine tracks patient visits and can be used to generate population reports for specified indicators such as cognitive decline or caregiver burnout.
"The number of older adults is growing rapidly. Delivering personalized care to this population is difficult and requires the ability to track a large number of mental and physical indicators," said Regenstrief Institute investigator Malaz Boustani, M.D., MPH, associate director of the IU Center for Aging Research and associate professor of medicine at the IU School of Medicine. He is senior author of the new study. "The software we have developed will help care coordinators measure the many needs of patients and their loved ones and monitor the effectiveness of individualized care plans."
In clinical trials over the past decade, Regenstrief and the IU Center for Aging Research investigator-clinicians developed and demonstrated the efficacy of an Alzheimer’s disease collaborative care model called the Aging Brain Care Medical Home. A hallmark of the ABC-MedHome is the employment of care coordinators who help clinicians identify and manage processes and protocols for Alzheimer’s patients who receive care in local primary care physician offices. The ABC-MedHome has been shown to improve the quality of Alzheimer’s care and decrease its burden on the health care system.
Within the ABC-MedHome program, Dr. Boustani and colleagues have now developed, tested, implemented and improved software that is sensitive to the clinical needs of a multispecialty team of professionals who provide care to complex patients across a variety of settings. The new software allows tracking of individual patient health outcomes as well as the ability to follow the status of an entire patient population with key quality, health and cost metrics.
"Integration of the eMR-ABC program within Wishard-Eskenazi Health was pivotal to our receipt in 2012 of a Health Care Innovation Challenge award from the Centers for Medicare & Medicaid Services to expand from care of 250 patients to 2,000 patients plus caregivers," said Dr. Boustani, who is medical director of the Wishard Healthy Aging Brain Center and also an IU Health geriatrician. "New models of care, supported by population health management tools, are needed if we are to provide improved quality of care and encourage better health outcomes for our patients and be cost sensitive. We are using health information technology to manage high-risk populations while achieving the triple aim of better health and better care at lower cost."
(Source: eurekalert.org)
Psychology Prof. Richard Russell reveals a new sign of aging in perception research
The contrasting nature of facial features is one of the signals that people unconsciously use to decipher how old someone looks, says Psychology Prof. Richard Russell, who has been collaborating with researchers from CE.R.I.E.S. (Epidermal and Sensory Research and Investigation Center), a department of Chanel Research and Technology dedicated to skin related issues and facial appearance.
“Unlike with wrinkles, none of us are consciously aware that we’re using this cue, even though it stares us in the face every day,” said Russell.
The discovery of this cue to facial age perception may partly explain why cosmetics are worn the way they are, and it lends more evidence to the idea that makeup use reflects our biological as well as our cultural heritage, according to Russell.
In one study, Russell and his team measured images of 289 faces ranging in age from 20 to 70 years old, and found that through the aging process, the color of the lips, eyes and eyebrows change, while the skin becomes darker. This results in less contrast between the features and the surrounding skin – leaving older faces to have less contrast than younger faces.
The difference in redness between the lips and the surrounding skin decreases, as does the luminance difference between the eyebrow and the forehead, as the face ages. Although not consciously aware of this sign of aging, the mind uses it as a cue for perceiving how old someone is.
In another study involving more than a hundred subjects in Gettysburg and Paris, the scientists artificially increased these facial contrasts and found that the faces were perceived as younger. When they artificially decreased the facial contrasts, the faces were perceived as older.
The image shows two identical images of the same face, except that the facial contrast has been increased in the left image and decreased in the right image. The face on the left appears younger than the one on the right.
Cosmetics are commonly used to increase aspects of facial contrast, such as the redness of lips. Scientists propose that this can partly explain why makeup is worn the way that it is – shades of lipstick that increase the redness of the lips are making the face appear younger, which is related to healthiness and beauty.
More on Russell’s study is available from PLOS ONE, an open-access publisher that makes the world’s scientific and medical literature a public resource.
New Study Validates Longevity Pathway
A new study demonstrates what researchers consider conclusive evidence that the red wine compound resveratrol directly activates a protein that promotes health and longevity in animal models.
What’s more, the researchers have uncovered the molecular mechanism for this interaction, and show that a class of more potent drugs currently in clinical trials act in a similar fashion. Pharmaceutical compounds similar to resveratrol may potentially treat and prevent diseases related to aging in people, the authors contend.
These findings are published in the March 8 issue of Science.
For the last decade, the science of aging has increasingly focused on sirtuins, a group of genes that are believed to protect many organisms, including mammals, against diseases of aging. Mounting evidence has demonstrated that resveratrol, a compound found in the skin of grapes as well as in peanuts and berries, increases the activity of a specific sirtuin, SIRT1, that protects the body from diseases by revving up the mitochondria, a kind of cellular battery that slowly runs down as we age. By recharging the batteries, SIRT1 can have profound effects on health.
Mice on resveratrol have twice the endurance and are relatively immune from effects of obesity and aging. In experiments with yeast, nematodes, bees, flies and mice, lifespan has been extended.
“In the history of pharmaceuticals, there has never been a drug that binds to a protein to make it run faster in the way that resveratrol activates SIRT1,” said David Sinclair, Harvard Medical School professor of genetics and senior author on the paper. “Almost all drugs either slow or block them.”
In 2006, Sinclair’s group published a study showing that resveratrol could extend the lifespan of mice, and the company Sirtris Pharmaceuticals, which was started by HMS researchers, was founded to make drugs more potent than resveratrol. (Sinclair is a co-founder of Sirtris, a GlaxoSmithKline company, and remains a scientific advisor. Sirtris currently has a number of sirtuin-activating compounds in clinical trials.)
But while numerous studies, from Sinclair’s lab and elsewhere, underscored a direct causal link between resveratrol and SIRT1, some scientists claimed the studies were flawed.
The contention lay in the way SIRT1 was studied in vitro, using a specific chemical group attached to the targets of SIRT1 that fluoresces more brightly as SIRT1 activity increases. This chemical group, however, is synthetic and does not exist in cells or in nature, and without it the experiments did not work. As a response to this, a paper published in 2010 surmised that resveratrol’s activation of SIRT1 was an experimental artifact, one that existed in the lab, but not in an actual animal. SIRT1 activity in mice was, the paper claimed, at best an indirect result of resveratrol, and perhaps even a sheer coincidence.
As a result, a debate erupted over the particular pathway that resveratrol and similar compounds affected. Does resveratrol directly activate SIRT1 or is the effect indirect? “We had six years of work telling us that this was most definitely not an artifact,” said Sinclair. “Still, we needed to figure out precisely how resveratrol works. The answer was extremely elegant.”
Sinclair and Basil Hubbard, then a doctoral student in the lab, teamed up with a group of researchers from both the National Institutes of Health and Sirtris Pharmaceuticals to address this question.
First, the team addressed the problem of the fluorescent chemical group. Why was it required for resveratrol to rev up SIRT1 in the test tube? Instead of dismissing the result as an artifact, the researchers surmised that the chemical might be mimicking molecules found naturally in the cell. These turned out to be a specific class of amino acid, the building blocks of proteins. In nature, there are three amino acids that resemble the fluorescent chemical group, one of which is tryptophan, a molecule abundant in turkey and notable for inducing drowsiness. When researchers repeated the experiment, swapping the fluorescing chemical group on the substrate with a tryptophan residue, resveratrol and similar molecules were once again able to activate SIRT1.
“We discovered a signature for activation that is in fact found in the cell and doesn’t require these other synthetic groups,” said Hubbard, first author of the study. “This was a critical result, which allowed us to bridge the gap between our biochemical and physiological findings.
“Next, we needed to identify precisely how resveratrol presses on SIRT1’s accelerator,” said Sinclair. The team tested approximately 2,000 mutants of the SIRT1 gene, eventually identifying one mutant that completely blocked resveratrol’s effect. The particular mutation resulted in the substitution of a single amino acid residue, out of the 747 that make up SIRT1. The researchers also tested hundreds of other molecules from the Sirtris library, many of which are far more powerful than resveratrol, against this mutant SIRT1. All failed to activate it.
The authors propose a model for how resveratrol works: When the molecule binds, a hinge flips, and SIRT1 becomes hyperactive.
Although these experiments occurred in a test tube, once the researchers identified the precise location of the accelerator pedal on SIRT1—and how to break it—they could test their ideas in a cell. They replaced the normal SIRT1 gene in muscle and skin cells with the accelerator-dead mutant. Now they could test precisely whether resveratrol and the drugs in development work by tweaking SIRT1 (in which case they would not work) or one of the thousands of other proteins in a cell (in which they would work). While resveratrol and the drugs tested revved up mitochondria in normal cells (an effect caused activating by SIRT1), the mutant cells were completely immune.
“This was the killer experiment,” said Sinclair. “There is no rational alternative explanation other than resveratrol directly activates SIRT1 in cells. Now that we know the exact location on SIRT1 where and how resveratrol works, we can engineer even better molecules that more precisely and effectively trigger the effects of resveratrol.”
The researchers plan on continuing academic-industry collaborations with the goal of bringing to fruition drugs that treat diseases associated with aging.
Age-Related Dementia May Begin with Neurons’ Inability to Rid Themselves of Unwanted Proteins
A team of European scientists from the University Medical Center Hamburg-Eppendorf (UKE) and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) at the University of Cologne in Germany has taken an important step closer to understanding the root cause of age-related dementia. In research involving both worms and mice, they have found that age-related dementia is likely the result of a declining ability of neurons to dispose of unwanted aggregated proteins. As protein disposal becomes significantly less efficient with increasing age, the buildup of these unwanted proteins ultimately leads to the development and progression of dementia. This research appears in the March 2013 issue of the journal Genetics.
“By studying disease progression in dementia, specifically by focusing on mechanisms neurons use to dispose of unwanted proteins, we show how these are interconnected and how these mechanisms deteriorate over time,” said Markus Glatzel, M.D., a researcher involved in the work from the Institute of Neuropathology at UKE in Hamburg, Germany. “This gives us a better understanding as to why dementias affect older persons; the ultimate aim is to use these insights to devise novel therapies to restore the full capacity of protein disposal in aged neurons.”
To make this discovery, scientists carried out their experiments in both worm and mouse models that had a genetically-determined dementia in which the disease was caused by protein accumulation in neurons. In the worm model, researchers in the lab of Thorsten Hoppe, Ph.D., from the CECAD Cluster of Excellence could inactivate distinct routes used for the disposal of the unwanted proteins. Results provided valuable insight into the mechanisms that neurons use to cope with protein accumulation. These pathways were then assessed in young and aged mice. This study provides an explanation of why dementias exponentially increase with age. Additionally, neuron protein disposal methods may offer a therapeutic target for the development of drugs to treat and/or prevent dementias.
“This is an exciting study that helps us understand what’s going wrong at a cellular level in age-related dementias,” said Mark Johnston, Ph.D., Editor-in-Chief of the journal Genetics. “This research holds possibilities for future identification of substances that can prevent, stop, or reverse this cellular malfunction in humans.”
(Image: damato)
A proposed link between aging, autism, and oxidation
Like any factory, the body burns oxygen to get energy for its various needs. As a result, detrimental byproducts are released and our cells try to clean up shop with antioxidants. But as we age, this process becomes a losing battle.
“Oxidation inexorably moves us along toward an oxidized state,” said pharmaceutical sciences professor Richard Deth. “You have to deal with it progressively.”
One option is to slow down the synthesis of new proteins, a process that requires energy. Indeed, as we age, we produce fewer new proteins, which explains why our capacity for learning and healing suffer as we grow old.
Since every protein originates from instructions in the DNA, protein synthesis can be slowed down by turning off particular genes. A process called epigenetic regulation accomplishes the task by adding molecular tags on top of the genome. The protein methionine synthase regulates this process. But what regulates methionine synthase? Oxidation.
“This enzyme is the most easily oxidized molecule in the body,” said Deth, whose research on the subject was recently published in the journal PLOS ONE. The senior author for the study, Christina Muratore, received her doctorate in pharmaceutical sciences from Northeastern in 2010.
Whenever the body is under oxidative stress, Deth explained, methionine synthase, or MS, stops working. He and his team hypothesized that MS plays an important regulatory role in aging and that it might be impaired in autism, which Deth has connected to unchecked oxidative stress in previous research.
To examine their hypothesis, the researchers looked at postmortem human brain samples across the lifespan, with subjects as young as 28 weeks of fetal development to as old as 84 years. They measured the levels of a molecule called MS mRNA, which transcribes the genetic code for methionine synthase into actual protein.
As the subjects aged, their brain tissue showed lower levels of MS mRNA. But, surprisingly, the levels of the protein itself remained constant across the lifespan.
Deth and his colleagues suspect that this observed decrease in MS mRNA over our lives may act as a check in the system to save energy that we no longer have in plentiful supply and to slow down oxidative stress. “One way that the system can guard against too much protein synthesis is to restrict the amount of mRNA,” Deth said.
The team also compared MS protein and mRNA levels between brain tissue samples from autistic and normally developing subjects. Autistic brains had markedly less MS mRNA than the control samples but similar protein levels. Additionally, the age-dependent trend seen in normally developing brains was not mimicked among the autistic sample.
If decreased MS mRNA does mean decreased protein production, it’s no big deal for adults who don’t need to make new proteins as often. But for the developing brain, new proteins are critical. “Your capacity for learning might be prematurely reduced because metabolically you can’t afford it,” Deth suggested.
While the results are preliminary and will benefit from repeated studies and more investigation, Deth’s findings add to a growing body of evidence linking both aging and autism to oxidative stress.
Study looks to distinguish cognitive functioning in centenarians
As life expectancy continues to increase, more and more people will reach and surpass the century mark in age. But even as greater numbers reach and surpass the 100-year milestone, little is known about what constitutes normal levels of cognitive function in the second century of life.
Led by Adam Davey, associate professor in Temple’s Department of Public Health, a group of researchers used a new method called factor mixture analysis — a statistical technique for identifying different groups within a population — to identify the prevalence of cognitive impairment in centenarians and try to understand the cognitive changes that are part of extreme aging. They published their findings, “Profiles of Cognitive Functioning in a Population-Based Sample of Centenarians Using Factor Mixture Analysis,” in the journal Experimental Aging Research.
“One of the motivations for studying centenarians is that they are very close to the upper limit of human life expectancy right now,” said Davey. “By looking at their cognitive functioning we can learn a lot in terms of how common or prevalent cognitive impairment is among that age group.”
Using voter registration lists and nursing home records in 44 counties in northern Georgia, the researchers identified 244 people between the ages of 98-108 — approximately 20 percent of all centenarians living in that region — who participated in the study. Participants were assessed based on a series of standard tests used to measure cognitive functioning.
“As people get into later life and the prevalence of cognitive impairment becomes relatively high, we need some way of distinguishing between those people who are aging normally and the people who have cognitive impairment, which could indicate dementia,” said Davey.
The researchers found that even though approximately two-thirds of centenarians were at or below the threshold for cognitive impairment by one commonly used measure, only one-third of centenarians were identified as cognitively impaired using their new approach.
“That’s consistent with the level of cognitive impairment found in another study that looked at people up to the age of 85-plus,” said Davey. “But even the normal folks have had cognitive declines to the point that they are functioning at a level that would indicate impairment at younger ages.”
The researchers found that characteristics such as age, race and educational attainment can help to distinguish those in the lower cognitive performance group.
“This is the first study that I’m aware of that allows us to distinguish between these two groups of centenarians, so that we can start to develop benchmarks for what is normal cognitive functioning among members of this age group,” said Davey. “These people have lived so long that even their normal cognitive function could be mistaken for a form of dementia if a physician were to treat them as they would someone who was merely old.”
(Image credit: Krissy_77)