November 18, 2017
November 18, 2017
March 30, 2017
A research team led by Harvard Medical School professor of genetics David Sinclair, PhD, has made a discovery that could lead to a revolutionary new drug that allows cells to repair DNA damaged by aging, cancer, and radiation.
In a paper published in the journal Science on Friday (March 24), the scientists identified a critical step in the molecular process related to DNA damage.
The researchers found that a compound known as NAD (nicotinamide adenine dinucleotide), which is naturally present in every cell of our body, has a key role as a regulator in protein-to-protein interactions that control DNA repair. In an experiment, they found that treating mice with a NAD+ precursor called NMN (nicotinamide mononucleotide) improved their cells’ ability to repair DNA damage.
“The cells of the old mice were indistinguishable from the young mice, after just one week of treatment,” said senior author Sinclair.
Human trials of NMN therapy will begin within the next few months to “see if these results translate to people,” he said. A safe and effective anti-aging drug is “perhaps only three to five years away from being on the market if the trials go well.”
What it means for astronauts, childhood cancer survivors, and the rest of us
The researchers say that in addition to reversing aging, the DNA-repair research has attracted the attention of NASA. The treatment could help deal with radiation damage to astronauts in its Mars mission, which could cause muscle weakness, memory loss, and other symptoms (see “Mars-bound astronauts face brain damage from galactic cosmic ray exposure, says NASA-funded study“), and more seriously, leukemia cancer and weakened immune function (see “Travelers to Mars risk leukemia cancer, weakend immune function from radiation, NASA-funded study finds“).
The treatment could also help travelers aboard aircraft flying across the poles. A 2011 NASA study showed that passengers on polar flights receive about 12 percent of the annual radiation limit recommended by the International Committee on Radiological Protection.
The other group that could benefit from this work is survivors of childhood cancers, who are likely to suffer a chronic illness by age 45, leading to accelerated aging, including cardiovascular disease, Type 2 diabetes, Alzheimer’s disease, and cancers unrelated to the original cancer, the researchers noted.
For the past four years, Sinclair’s team has been working with spinoff MetroBiotech on developing NMN as a drug. Sinclair previously made a link between the anti-aging enzyme SIRT1 and resveratrol. “While resveratrol activates SIRT1 alone, NAD boosters [like NMN] activate all seven sirtuins, SIRT1-7, and should have an even greater impact on health and longevity,” he says.
Sinclair is also a professor at the University of New South Wales School of Medicine in Sydney, Australia.
Abstract of A conserved NAD+ binding pocket that regulates protein-protein interactions during aging
DNA repair is essential for life, yet its efficiency declines with age for reasons that are unclear. Numerous proteins possess Nudix homology domains (NHDs) that have no known function. We show that NHDs are NAD+ (oxidized form of nicotinamide adenine dinucleotide) binding domains that regulate protein-protein interactions. The binding of NAD+ to the NHD domain of DBC1 (deleted in breast cancer 1) prevents it from inhibiting PARP1 [poly(adenosine diphosphate–ribose) polymerase], a critical DNA repair protein. As mice age and NAD+ concentrations decline, DBC1 is increasingly bound to PARP1, causing DNA damage to accumulate, a process rapidly reversed by restoring the abundance of NAD+. Thus, NAD+ directly regulates protein-protein interactions, the modulation of which may protect against cancer, radiation, and aging.
December 18, 2016
Wrinkles, grey hair and niggling aches are normally regarded as an inevitable part of growing older, but now scientists claim that the ageing process may be reversible.
The team showed that a new form of gene therapy produced a remarkable rejuvenating effect in mice. After six weeks of treatment, the animals looked younger, had straighter spines and better cardiovascular health, healed quicker when injured, and lived 30% longer.
Juan Carlos Izpisua Belmonte, who led the work at the Salk Institute in La Jolla, California, said: “Our study shows that ageing may not have to proceed in one single direction. With careful modulation, ageing might be reversed.”
The genetic techniques used do not lend themselves to immediate use in humans, and the team predict that clinical applications are a decade away. However, the discovery raises the prospect of a new approach to healthcare in which ageing itself is treated, rather than the various diseases associated with it.
The findings also challenge the notion that ageing is simply the result of physical wear and tear over the years. Instead, they add to a growing body of evidence that ageing is partially – perhaps mostly – driven by an internal genetic clock that actively causes our body to enter a state of decline.
The scientists are not claiming that ageing can be eliminated, but say that in the foreseeable future treatments designed to slow the ticking of this internal clock could increase life expectancy.
“We believe that this approach will not lead to immortality,” said Izpisua Belmonte. “There are probably still limits that we will face in terms of complete reversal of ageing. Our focus is not only extension of lifespan but most importantly health-span.”
Wolf Reik, a professor of epigenetics at the Babraham Institute, Cambridge, who was not involved in the work, described the findings as “pretty amazing” and agreed that the idea of life-extending therapies was plausible. “This is not science fiction,” he said.
The rejuvenating treatment given to the mice was based on a technique that has previously been used to “rewind” adult cells, such as skin cells, back into powerful stem cells, very similar to those seen in embryos. These so-called induced pluripotent stem (iPS) cells have the ability to multiply and turn into any cell type in the body and are already being tested in trials designed to provide “spare parts” for patients.
The latest study is the first to show that the same technique can be used to partially rewind the clock on cells – enough to make them younger, but without the cells losing their specialised function.
“Obviously there is a logic to it,” said Reik. “In iPS cells you reset the ageing clock and go back to zero. Going back to zero, to an embryonic state, is probably not what you want, so you ask: where do you want to go back to?”
The treatment involved intermittently switching on the same four genes that are used to turn skin cells into iPS cells. The mice were genetically engineered in such a way that the four genes could be artificially switched on when the mice were exposed to a chemical in their drinking water.
The scientists tested the treatment in mice with a genetic disorder, called progeria, which is linked to accelerated ageing, DNA damage, organ dysfunction and dramatically shortened lifespan.
After six weeks of treatment, the mice looked visibly younger, skin and muscle tone improved and they lived 30% longer. When the same genes were targeted in cells, DNA damage was reduced and the function of the cellular batteries, called the mitochondria, improved.
“This is the first time that someone has shown that reprogramming in an animal can provide a beneficial effect in terms of health and extend their lifespan,” said Izpisua Belmonte.
Crucially, the mice did not have an increased cancer risk, suggesting that the treatment had successfully rewound cells without turning them all the way back into stem cells, which can proliferate uncontrollably in the body.
The potential for carcinogenic side-effects means that the first people to benefit are likely to be those with serious genetic conditions, such as progeria, where there is more likely to be a medical justification for experimental treatments. “Obviously the tumour risk is lurking in the background,” said Reik.
The approach used in the mice could not be readily applied to humans as it would require embryos to be genetically manipulated, but the Salk team believe the same genes could be targeted with drugs.
“These chemicals could be administrated in creams or injections to rejuvenate skin, muscle or bones,” said Izpisua Belmonte. “We think these chemical approaches might be in human clinical trials in the next ten years.”
The findings are published in the journal Cell.
This article was amended on 16 December 2016. A previous version erroneously gave Wolf Reik’s affiliation as the University of Cambridge. This has now been corrected to the Babraham Institute, Cambridge.
April 23, 2016
Could there be a recipe for a longer, healthier life?
Pop a pill and live a long, healthy life. It might not be quite that easy yet, but researchers at Mayo Clinic believe they have found a cell that could hold the secret to aging extra gracefully.
Their research, published in the journal Nature Wednesday, helped patients live longer, healthier lives. The only catch is their patients are mice. But the researchers believe they could someday translate it into a recipe for human longevity, too.
In fact, the research has been so convincing that Mayo Clinic invested in Unity Biotechnology, a San Francisco-based startup built around the researchers’ approach. Other investors in the company include ARCH Venture Partners, Venrock, and Chinese WuXi, and the study’s lead author Jan van Deursen is listed as a Unity co-founder.
The anti-aging method works like this: scientists inject the mice with a drug that pushes out toxic, worn-out cells called “senescent cells.” The senescent cells are old and stressed and don’t behave properly anymore. Instead, they “litter the body with aging” as van Deursen puts it.
Mice that had their senescent cells routinely flushed starting in middle age grew to be much healthier in their older age. They were not only more active and exploratory, they also developed tumors more slowly than control mice. They experienced fewer eyesight problems, less fat buildup, and improved heart and kidney health. On average, these mice lived eight months longer than those that received no drugs. In mouse terms, that’s a one-third longer lifespan.
Because of the way the drug attacks the senescent cells, the mice cocktail won’t work in humans—at least not yet. But Unity proposes to find ways to combat age-related diseases and disabilities by learning more about how these senescent cells behave in people, research that could take years, even decades.
“Imagine drugs that could prevent, maybe even cure, arthritis or heart disease or loss of eyesight,” says Nathaniel David, Unity’s co-founder and CEO. “It’s an incredible aspiration.”
The research team first eliminated senescent cells from genetically modified mice back in 2011 and this new research is their first attempt on healthy, regular mice.
And they have been at it longer than their nearest Silicon Valley competition, Calico, the ultra-secret “California Life Company” started by Alphabet CEO Larry Page and Apple Chairman Arthur Levinson in 2013. Calico has partnered with several drug researchers, such as the pharmaceutical company AbbVie. They have also hired lab researchers to work on anti-aging drugs, though the company hasn’t brought anything to market yet.
And this isn’t just California dreaming—it has the capacity to help us all. “If we can translate this biology into medicines, our children might grow up in significantly better health as they age,” says David. “There will be many obstacles to overcome, but our team is committed and inspired to achieve our mission.”
December 13, 2015
To most of the scientific community, “anti-aging” is a dirty word.
A medical field historically associated with charlatans and quacks, scientists have strictly restricted the quest for a “longevity pill” to basic research. The paradigm is simple and one-toned: working on model organisms by manipulating different genes and proteins, scientists slowly tease out the molecular mechanisms that lead to — and reverse — signs of aging, with no guarantee that they’ll work in humans.
But it’s been a fruitful search: multiple drug candidates, many already on the market for immune or psychiatric disorders, have consistently delayed age-associated diseases and stretched the lifespan of fruit flies, roundworms and mice. Yet human trials have been far beyond reach — without the FDA acknowledging “aging” as a legitimate target for drug development, researchers have had no way of pitching clinical trials to the regulatory agency.
This year, the FDA green lighted an audacious proposal that seeks to test in 3,000 volunteers a drug that — based on animal studies — could extend human lifespan by up to 40 percent and decrease chances of getting age-related diseases. The double-blind, multi-centered trial, Targeting Aging with Metformin (TAME), is the first that pushes aging as a bona fide disease — one that may eventually be tamed with drugs.
“We think this is a groundbreaking, perhaps paradigm-shifting trial,” said Dr. Steven Austad, scientific director of the American Federation for Aging Research (AFAR).
Without a doubt, TAME is an odd one in the realm of clinical trials. Spearheaded by Dr. Nil Barzilai, an ebullient scientist based at the Albert Einstein College of Medicine, TAME receives no support from the pharmaceutical industry. The brainchild of a team made up solely of academics, TAME is sponsored by the nonprofit organization AFAR.
Even more of a head scratcher is this: if the drug were to work in humans — making it the first scientifically proven longevity pill, an elixir worth billions — none of the team members stand to make any money. This is because metformin, the star of the trial, is a generic diabetes drug that costs only a few cents a dose.
It’s not about the money; it’s something far bigger.
What we’re talking about here is an idea that fundamentally changes how we look at aging and disease, said Dr. S. Jay Olshansky, a biodemographer at the University of Illinois and TAME team member.
The idea is this: rather than tackling the top medical killers — cancer, cardiovascular disease, dementia — individually, we should instead focus on slowing or reversing the single most prominent risk factor associated with all those diseases — age.
It may be as close to a silver bullet as we’ll get.
TAME is built on decades of basic research on aging, mostly conducted in short-lived model organisms such as fruit flies, nematode worms and mice. By individually tweaking genes and measuring the resulting effects on healthspan and lifespan, scientists gradually teased out individual molecular pathways that drive aging forward.
Within the last few years, the field has built a solid theoretical framework of the aging process. Endearingly known as the “major pillars of aging,” the framework includes pathways related to metabolism, stress response, inflammation, stem cell quality and proteomic homeostasis — that is, the body’s ability to keep groups of proteins functioning in harmony.
Yet scientists have not yet teased out the so-called “master regulators,” or central cross points that bridge the different pathways and drive aging forward.
Some of us think that the brain is the central regulator, that inflammatory processes in the hypothalamus are sufficient to drive aging of the body, said Dr. Dongsheng Cai, a neuroscientist at the Albert Einstein College of Medicine.
Our current anti-aging apothecary contains antidepressants, said Dr. Michael Petrascheck, a researcher at the Scripps Institute, to Singularity Hub. And we think those drugs act on the brain, which in turn regulates gene expression in the body to increase stress resistance and increase lifespan.
Others, in contrast, think pro-aging factors in the blood drive brain aging. Last year, a series of groundbreaking studies laid bare the rejuvenating effects of young blood. When researchers diluted the blood of an old mouse by infusing it with blood from a young mouse, the old mouse’s brain, blood vessels and muscles all reverted back to a younger state.
Although master regulators remain elusive, research has uncovered an impressive list of drug candidates. Metformin, TAME’s test drug, sits solidly at the top of that list.
It’s a truly ancient drug. Widely used in humans since the Middle Ages, metformin reduces blood sugar and works on multiple pathways involved in cell growth, inflammation and metabolism — all of which constitute the major pillars of aging.
Epidemiological studies suggest that metformin reduces the risk of cancer and dementia. What’s more, a large 2014 study of 78,000 people showed that on average, people with Type 2 diabetes who take the drug live longer than those of the same age who don’t.
Metformin seems to fit the bill of a longevity drug. But it was the chemical’s two other perks that made it a winner to the TAME team.
First, it’s very safe. When taken as prescribed, the drug has few side effects, and those that do occur are well documented.
Second, and perhaps the kicker, is that in addition to extending lifespan, it also extends healthspan — the number of years that an organism remains healthy, even in old age.
Our goal is not to extend life per se, explained Olshansky. In fact, that was the basis of our proposal to the FDA, he laughed.
TAME is based on a promising — if surprising — result repeatedly found in multiple organisms: increases in lifespan have often been associated with increased healthspan. That is, with some manipulations such as caloric restriction, not only have the animals lived longer, they also stayed mentally sharp and able-bodied in those extended years.
If this holds in humans, it could fundamentally change our health care system, said Olshansky.
In many people’s minds aging is not a disease, it’s simply humanity, said Barzilai. So instead of pitching a drug trial that targets aging to the FDA, we proposed to look at comorbidities — that is, chronic diseases that sharply rise in incidence as people age.
The goal is to see whether metformin delays the onset of age-related comorbidities. This strategy, part of a concept called the “longevity dividend,” was first proposed by Olshanky and colleagues back in 2006. The concept argues that slowing the process of aging has significant benefits in terms of health and wealth for individuals and the health care economy as a whole.
In a 2013 paper published in Health Affairs, Olshansky broke down the numbers. Based on animal models, even a small delay in aging could raise life expectancy by an additional 2.2 years, most of which is spent in good health. Over fifty years, the economic value of delaying aging is estimated to be $7.1 trillion. In contrast, targeting comorbidities separately — for example, heart disease and cancer —would end in diminishing improvements in health by 2060, mainly due to competing risks, argues Olshansky. It’s basically changing one disease for another.
“We’re not arguing — and we’ve never argued — that we’re trying to achieve life extension,” said Olshansky in an interview with Science News. “We’ll probably live a little longer if we succeed, but that’s not the goal. The goal is the extension of the period of healthy life.”
If TAME goes well, it’s only the first step towards battling aging in humans.
In addition to testing the effects of metformin, the TAME team also plans to take muscle and fat biopsies of volunteers before and after taking the drug. By using a big-data technique called RNA deep sequencing, which looks at what genes are expressed at what levels, the team hopes to identify biological “fingerprints” for aging.
Gene expression is like an orchestra — some groups of genes always turn on together, others always shut off. With age, however, gene expression patterns slowly drift out of whack, a phenomenon that researchers call “transcriptional drift.”
Reversing transcriptional drift is a great readout when trying to test the effects of new longevity drug candidates, said Petrascheck. In a study published this week, Petrascheck identified miaserin, an antidepressant already on the market, as a new type of “longevity pill” that extends young adulthood in worms without affecting later years.
Without a doubt, data from TAME will be incredibly valuable for judging other anti-aging drug candidates.
Regardless of how the trial turns out, the TAME team is optimistic.
The main reason we set out on this is to convince the FDA to approve aging as an indication, so that it can be a target for future trials with even better medications said Barzilai.
We got it, he said.
December 06, 2015
October 18, 2015
Following an exhaustive, ten-year effort, scientists at the Buck Institute for Research on Aging and the University of Washington have identified 238 genes that, when removed, increase the replicative lifespan of S. cerevisiae yeast cells. This is the first time 189 of these genes have been linked to aging. These results provide new genomic targets that could eventually be used to improve human health. The research was published online on October 8th in the journal Cell Metabolism.
“This study looks at aging in the context of the whole genome and gives us a more complete picture of what aging is,” said Brian Kennedy, PhD, lead author and the Buck Institute’s president and CEO. “It also sets up a framework to define the entire network that influences aging in this organism.”
The Kennedy lab collaborated closely with Matt Kaeberlein, PhD, a professor in the Department of Pathology at the University of Washington, and his team. The two groups began the painstaking process of examining 4,698 yeast strains, each with a single gene deletion. To determine which strains yielded increased lifespan, the researchers counted yeast cells, logging how many daughter cells a mother produced before it stopped dividing.
“We had a small needle attached to a microscope, and we used that needle to tease out the daughter cells away from the mother every time it divided and then count how many times the mother cells divides,” said Dr. Kennedy. “We had several microscopes running all the time.”
These efforts produced a wealth of information about how different genes, and their associated pathways, modulate aging in yeast. Deleting a gene called LOS1 produced particularly stunning results. LOS1 helps relocate transfer RNA (tRNA), which bring amino acids to ribosomes to build proteins. LOS1 is influenced by mTOR, a genetic master switch long associated with caloric restriction and increased lifespan. In turn, LOS1 influences Gcn4, a gene that helps govern DNA damage control.
“Calorie restriction has been known to extend lifespan for a long time.” said Dr. Kennedy. “The DNA damage response is linked to aging as well. LOS1 may be connecting these different processes.”
A number of the age-extending genes the team identified are also found in C. elegans roundworms, indicating these mechanisms are conserved in higher organisms. In fact, many of the anti-aging pathways associated with yeast genes are maintained all the way to humans.
The research produced another positive result: exposing emerging scientists to advanced lab techniques, many for the first time.
“This project has been a great way to get new researchers into the field,” said Dr. Kennedy. “We did a lot of the work by recruiting undergraduates, teaching them how to do experiments and how dedicated you have to be to get results. After a year of dissecting yeast cells, we move them into other projects.”
Though quite extensive, this research is only part of a larger process to map the relationships between all the gene pathways that govern aging, illuminating this critical process in yeast, worms and mammals. The researchers hope that, ultimately, these efforts will produce new therapies.
“Almost half of the genes we found that affect aging are conserved in mammals,” said Dr. Kennedy. “In theory, any of these factors could be therapeutic targets to extend healthspan. What we have to do now is figure out which ones are amenable to targeting.”
Other Buck Institute researchers involved in the study include: Mark A. McCormick (first co-author), Mitsuhiro Tsuchiya, Scott Tsuchiyama, Arianna Anies, Juniper K. Pennypacker, Shiena Enerio, Dan Lockshon, Brett Robinson, Ariana A. Rodriguez, Marc K. Ting, and Rachel B. Brem. A full list of authors is included in the paper.
This research was supported by NIH grants R01AG043080, R01AG025549, R01AG039390 and P30AG013280, as well as NIH training grants T32AG000266, T32AG000057 and T32ES007032 and the Ellison Medical Foundation.
August 27, 2015
Tony Wyss-Coray studies the impact of aging on the human body and brain. In this eye-opening talk, he shares new research from his Stanford lab and other teams which shows that a solution for some of the less great aspects of old age might actually lie within us all.
August 3, 2015
The question of why we age is one of the most fascinating questions for humankind, but nothing close to a satisfactory answer has been found to date. Scientists at the Leibniz-Institut für Molekulare Pharmakologie in Berlin have now taken one step closer to providing an answer. They have conducted a study in which, for the first time, they have shown that a certain area of the cell, the so-called endoplasmic reticulum, loses its oxidative power in advanced age. If this elixir of life is lost, many proteins can no longer mature properly. At the same time, oxidative damage accumulates in another area of the cell, the cytosol. This interplay was previously unknown and now opens up a new understanding of aging, but also of neurodegenerative diseases such as Alzheimer’s or Parkinson’s.
Each cell consists of different compartments. One of them is the endoplasmic reticulum (ER). Here, proteins which are then secreted e.g. into the bloodstream, such as insulin or antibodies of the immune system, mature in an oxidative environment. A type of quality control, so-called redox homoeostasis, ensures that the oxidative milieu is maintained and disulphide bridges can form. Disulphide bridges form and stabilise the three-dimensional protein structure and are thus essential for a correct function of the secretory proteins, e.g. those migrating into the blood.
Equilibrium thrown off balance
Scientists at the Leibniz-Institut für Molekulare Pharmakologie in Berlin have now shown, for the first time, that the ER loses its oxidative power in advanced age, which shifts the reducing/oxidising equilibrium — redox for short — in this compartment. This leads to a decline in the capacity to form the disulphide bridges that are so important for correct protein folding. As a consequence, many proteins can no longer mature properly and become unstable.
Although, it was already known that increased protein misfolding occurs with the progression of aging, it was not known whether the redox equilibrium is affected. Likewise, it was not known that the loss of oxidative power in the ER also affects the equilibrium in another compartment of the cell: in reverse, namely, the otherwise protein-reducing cytosol becomes more oxidising during aging, which leads to the known oxidative protein damage such those caused by the release of free radicals.
“Up to now, it has been completely unclear what happens in the endoplasmic reticulum during the aging process. We have now succeeded in answering this question,” says Dr. Janine Kirstein, first author of the study, which has been published in EMBO Journal*. At the same time, the scientists were able to show that there is a strong correlation between protein homoeostasis and redox equilibrium. “This is absolutely new and helps us to understand why secretory proteins become unstable and lose their function in advanced age and after stress. This may explain why the immune response declines as we get older,” the biologist explains further.
Stress has the same effects as aging
The researchers also demonstrated the decline of the oxidative milieu of the ER after stress. When they synthesised amyloid protein fibrils in the cell, which cause diseases such as Alzheimer’s, Parkinson’s or Huntington’s disease, they set the same cascade in motion. Apart from this, they were able to show that amyloids that are synthesised in a certain tissue also have negative effects on the redox equilibrium in another tissue within the same organism. “Protein stress leads to the same effects as aging,” explains Kirstein. “Our findings are thus not only interesting with regards to aging, but also concerning neurodegenerative diseases such as Alzheimer’s.”
For their experiments, the team of researchers used nematodes — an established model system for investigating aging processes on a molecular level. Since the nematode is transparent, the researchers were able to use fluorescence-based sensors in order to measure oxidation in the individual cell compartments. It was thus possible to track precisely in the living nematode how the redox condition changes with advancing age. In addition, the influence of protein aggregation on the redox homeostasis was investigated in cultivated cells of human origin. The data were fully consistent with those from the nematode.
Using the findings to identify new diagnostic biomarkers
“We gained a lot of insight, but have also learned that aging is much more complex than previously assumed,” stresses the biologist Kirstein. Thus, for example, the mechanism of the signal transduction of protein folding stress to the redox equilibrium — both within the cell from one compartment to another and also between two different tissues — remains completely unclear.
Nevertheless, research of aging has taken a major step forward as a result of the findings from Berlin, particularly since it promises a practical benefit. The redox equilibrium may serve as a basis for new biomarkers for diagnosing both aging and neurodegenerative processes in the future. Janine Kirstein: “The approach is less likely to be useful for therapeutic purposes at present, but the development of diagnostic tools is certainly conceivable.”
January 26, 2015
In the largest collaborative study of the brain to date, about 300 researchers in a global consortium of 190 institutions identified eight common genetic mutations that appear to age the brain an average of three years.
The discovery could lead to targeted therapies and interventions for Alzheimer’s disease, autism, and other neurological conditions.
Led by the Keck School of Medicine of the University of Southern California (USC), an international team known as the Enhancing Neuro Imaging Genetics through Meta Analysis (ENIGMA) Network, pooled brain scans and genetic data worldwide to pinpoint genes that enhance or break down key brain regions in people from 33 countries.
This is the first high-profile study since the National Institutes of Health (NIH) launched its Big Data to Knowledge (BD2K) centers of excellence in 2014. The research was published Wednesday, Jan. 21, in the peer-reviewed journal Nature.
“Our global team discovered eight genes that may erode or boost brain tissue in people worldwide,” said Paul Thompson, Ph.D., Keck School of Medicine of USC professor and principal investigator of ENIGMA. ” Any change in those genes appears to alter your mental bank account or brain reserve by 2 or 3 percent. The discovery will guide research into more personalized medical treatments for Alzheimer’s, autism, depression and other disorders.”
The study could help identify people who would most benefit from new drugs designed to save brain cells, but more research is necessary to determine if the genetic mutations are implicated in disease.
The ENIGMA researchers screened millions of “spelling differences” in the genetic code to see which ones affected the size of key parts of the brain in magnetic resonance images (MRIs) from 30,717 individuals.
The MRI analysis focused on genetic data from seven regions of the brain that coordinate movement, learning, memory and motivation. The group identified eight genetic variants associated with decreased brain volume, several found in over one-fifth of the world’s population. People who carry one of those eight mutations had, on average, smaller brain regions than brains without a mutation but of comparable age; some of the genes are implicated in cancer and mental illness.
In October 2014, the NIH invested nearly $32 million in its Big Data Initiative, creating 12 research hubs across the United States to improve the utility of biomedical data.
“The ENIGMA Center’s work uses vast datasets as engines of biomedical discovery; it shows how each individual’s genetic blueprint shapes the human brain,” said Philip Bourne, Ph.D., associate director for data science at the NIH. “This ‘Big Data’ alliance shows what the NIH Big Data to Knowledge (BD2K) Program envisions achieving with our 12 Centers of Excellence for Big Data Computing.”
Other USC co-authors include Derrek P. Hibar, Neda Jahanshad and Arthur Toga. ENIGMA was supported in part by a Consortium grant from the NIH BD2K Initiative, supported by a cross-NIH partnership, and by public and private agencies worldwide.
Abstract of Common genetic variants influence human subcortical brain structures
The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10−33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.