Posts Tagged ‘genetics’

As the result of a six-year long research process, Fredrick R. Schumacher, a cancer epidemiology researcher at Case Western Reserve University School of Medicine, and an international team of more than 100 colleagues have identified 63 new genetic variations that could indicate higher risk of prostate cancer in men of European descent. The findings, published in a research letter in Nature Genetics, contain significant implications for which men may need to be regularly screened because of higher genetic risk of prostate cancer. The new findings also represent the largest increase in genetic markers for prostate cancer since they were first identified in 2006.

The changes, known as genetic markers or SNPs (“snips”), occur when a single base in the DNA differs from the usual base at that position. There are four types of bases: adenine (A), thymine (T), guanine (G) and cytosine (C). The order of these bases determines DNA’s instructions, or genetic code. They can serve as a flag to physicians that a person may be at higher risk for a certain disease. Previously, about 100 SNPs were associated with increased risk of prostate cancer. There are 3 billion base pairs in the human genome; of these, 163 have now been associated with prostate cancer.

One in seven men will be diagnosed with prostate cancer during their lifetimes.

“Our findings will allow us to identify which men should have early and regular PSA screenings and these findings may eventually inform treatment decisions,” said Schumacher. Prostate-specific antigen (PSA) screenings measure how much PSA, a protein produced by both cancerous and noncancerous tissue in the prostate, is in the blood.

Adding the 63 new SNPs to the 100 that are already known allows for the creation of a genetic risk score for prostate cancer. In the new study, the researchers found that men in the top one percent of the genetic risk score had a six-fold risk-increase of prostate cancer compared to men with an average genetic risk score. Those who had the fewest number of these SNPs, or a low genetic risk score, had the lowest likelihood of having prostate cancer.

In a meta-analysis that combined both previous and new research data, Schumacher, with colleagues from Europe and Australia, examined DNA sequences of about 80,000 men with prostate cancer and about 60,000 men who didn’t have the disease. They found that men with cancer had a higher frequency of 63 different SNPs (also known as single nucleotide polymorphisms) that men without the disease did not have. Additionally, the more of these SNPs that a man has, the more likely he is to develop prostate cancer.

The researchers estimate that there are about 500-1,000 genetic variants possibly linked to prostate cancer, not all of which have yet been identified. “We probably only need to know 10 percent to 20 percent of these to provide relevant screening guidelines,” continued Schumacher, who is an associate professor in the Department of Population and Quantitative Health Sciences at Case Western Reserve School of Medicine.

Currently, researchers don’t know which of the SNPs are the most predictive of increased prostate cancer risk. Schumacher and a number of colleagues are working to rank those most likely to be linked with prostate cancer, especially with aggressive forms of the disease that require surgery, as opposed to slowly developing versions that call for “watchful waiting” and monitoring.

The research lays a foundation for determining who and how often men should undergo PSA tests. “In the future, your genetic risk score may be highly indicative of your prostate cancer risk, which will determine the intensity of PSA screening,” said Schumacher. “We will be working to determine that precise genetic risk score range that would trigger testing. Additionally, if you have a low score, you may need screening less frequently such as every two to five years.” A further implication of the findings of the new study is the possibility of precise treatments that do not involve surgery. “Someday it may be feasible to target treatments based on a patient’s prostate cancer genetic risk score,” said Schumacher.

In addition to the work in the new study, which targets men of European background, there are parallel efforts underway looking at genetic signals of prostate cancer in men of African-American and Asian descent.

http://thedaily.case.edu/researchers-identify-dozens-new-gene-changes-point-elevated-risk-prostate-cancer-men-european-descent/

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Exposure to early life trauma can lead to poor physical and mental health in some individuals, which can be passed on to their children. Studies in mice show that at least some of the effects of stress can be transmitted to offspring via environmentally-induced changes in sperm miRNA levels.

A new epigenetics study raises the possibility that the same is true in humans. It shows for the first time that the levels of the same two sperm miRNAs change in both men and mice exposed to early life stress. In mice, the negative effects of stress are transmitted to offspring. The study is published On May 23rd in Translational Psychiatry.

“The study raises the possibility that some of the vulnerability of children is due to Lamarckian type inheritance derived from their parents’ experiences,” said Larry Feig, Ph.D., professor of Developmental, Molecular and Chemical Biology at Tufts University School of Medicine and member of the Cell, Molecular and Developmental Biology and Neuroscience programs at the Sackler School of Graduate Biomedical Sciences at Tufts.

The human part of the study utilized the Adverse Childhood Experiences (ACE) questionnaire as an indicator of men’s early life trauma. The ACE Study questionnaire includes 10 yes or no questions about one’s experiences until the age of 18, including physical, verbal, or sexual abuse, and physical or emotional neglect. Other questions relate to one’s family members. Four or more yes answers put one at significantly increased risk for future mental and physical health problems. According to a ChildTrends research brief published in 2014, a remarkably high percentage (~10 percent) of the population report scores at or above this cutoff.

miRNAs constitute a newly appreciated type of gene regulator, where each miRNA controls a distinct set of genes. Until recently, sperm from fathers were thought to contribute only DNA to the mother’s egg upon fertilization, but new data in mice indicate that sperm also contribute miRNAs that influence the next generation. Sperm miRNA expression in humans is known to be affected by environmental factors, such as smoking and obesity, but no human study to date has documented the effects of stress.

The new study found that among 28 Caucasian male volunteers, the expression of two highly related sperm miRNAs, miR-449 and miR-34, were inversely proportional to the men’s ACE scores. Men with the most extensive early abuse (highest ACE scores) had as much as a 300-fold reduction in the two sperm miRNAs compared to men with the least abuse.

The idea that these changes can affect the next generation is supported by additional findings in the study, e.g.:

the same sperm miRNA changes that take place in men with high ACE scores also occur in mice exposed to early life social instability stress, which Feig’s lab has shown previously leads to anxiety and sociability defects in female offspring of stressed males for at least three generations;
these two sets of miRNAs are known to work together in mice to allow proper development of the brain and sperm;
in humans, miR-34c has been implicated in promoting early embryo development;
the mouse studies showed that the decline in these sperm miRNA levels is transmitted to the next generation; and
when these embryos mature, these miRNAs are also reduced in the sperm of their male offspring who pass on stress behaviors to their female offspring.
“This is the first study to show that stress is associated with altered levels of sperm miRNAs in humans. We are currently setting up a new, larger study in men, and additional experiments in mice that could yield further support for the idea that changes in these sperm miRNAs do, in fact, contribute to an elevation of stress-related disorders across generations,” said David Dickson, an M.D./Ph.D. student at Tufts and first author of the study.

“Looking to the future, we may be able to figure out a way to restore the low miRNA levels found in men exposed to extreme trauma, because epigenetic changes, such as stress-induced decreases in sperm miRNA expression, are reversible, unlike genetic changes that alter the DNA sequence,” Dickson added.

For example, obesity has been shown to alter specific sperm miRNA levels in men, while bariatric surgery and subsequent weight loss can reverse the changes. In addition, Isabelle Mansuy’s lab has reversed some of the negative effects of stress in mice across generations by exposing mice to an “enriched environment” that involves extensive social interactions, exercise and opportunities to explore their surroundings.

Feig pointed out that in addition to focusing on the potential transgenerational effects of stress, there is a growing appreciation that physicians should collect information on childhood trauma for the sake of the patients who are experiencing this early trauma.

This is because “childhood abuse, trauma and dysfunction adds to the risk of future physical and psychiatric maladies, and significant exposure to abusive and/or dysfunctional families is remarkably common. Moreover, sensitivity to PTSD has been shown to correlate with ACE score, implying the ACE questionnaire could be used as a screening tool to identify people who should take extra precaution to avoid potentially traumatic experiences,” he said.

“However, some people may not answer the ACE survey accurately due to inaccurate recall or because of the sensitive nature of many of the questions, particularly in settings that do not allow anonymity and/or where their answers could affect their future. Thus, discovery of unbiased markers for early trauma, like specific sperm miRNA content, could complement ACE surveys in some clinical settings to bolster preventative medicine,” he concluded.

The authors note that the relatively small sample size limits their ability to more deeply explore the association between ACE scores and miRNA expression. In addition, a longitudinal study with information on behavioral and psychological factors throughout adulthood, with repeated measurements of sperm miRNA content, could allow for further exploration on the effect of cumulative exposure to childhood trauma on miRNA.

Additional authors are Jessica Paulus, Sc.D., Tufts Medical Center as well as Tufts University School of Medicine and the Sackler School; Virginia Mensah, M.D., formerly in Feig’s lab with Women & Infants Hospital and the Warren Alpert Medical School at Brown University and now with the Reproductive Science Center of New Jersey; Janis Lem, Ph.D., Tufts Medical Center; Lorena Saavedra-Rodriguez, Ph.D., formerly a postdoctoral fellow in Feig’s laboratory at Tufts and now with a biopharmaceutical company; and Adrienne Gentry, D.O. and Kelly Pagidas, M.D., University of Louisville School of Medicine.

This study was supported by awards from the National Institute of Mental Health of the National Institutes of Health (R01MH107536), as well as the Tufts Center for Neuroscience Research (National Institute of Neurological Disorders and Stroke of the NIH, P30NS047243). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other funders.

Dickson, D.A., Paulus, J.K., Mensah, V., Lem, J., Saavedra-Rodriguez, L., Gentry, A., Pagidas, K., and Feig, L. A. (2018). Reduced levels of miRNAs 449 and 34 in sperm of mice and men exposed to early life stress. Translational Psychiatry. https://doi.org/10.1038/s41398-018-0146-2

https://now.tufts.edu/news-releases/early-life-trauma-men-associated-reduced-levels-sperm-micrornas

Writing in the journal eLife, the team reveals that this disease is caused by a recessive mutation in CAMK2A – a gene that is well known for its role in regulating learning and memory in animals. The findings suggest that dysfunctional CAMK2 genes may contribute to other neurological disorders, such as epilepsy and autism, opening up potential new avenues for treating these conditions.

“A significant number of children are born with growth delays, neurological defects and intellectual disabilities every year across the world,” explains senior author Bruno Reversade, Research Director at the Institute of Medical Biology and Institute of Molecular and Cell Biology, A*STAR, Singapore, who supervised the study. “While specific genetic mutations have been identified for some patients, the cause remains unknown in many cases. Identifying novel mutations would not only advance our understanding of neurological diseases in general, but would also help clinicians diagnose children with similar symptoms and/or carry out genetic testing for expecting parents.”

The team’s research began when they identified a pair of siblings who demonstrated neurodevelopmental delay with frequent, unexplained seizures and convulsions. While the structure of their bodies developed normally, they did not gain the ability to walk or speak. “We believed that the children had novel mutations in CAMK2A, and we wanted to see if this were true,” says Reversade.

The fully functional CAMK2A protein consists of multiple subunits. Using a genomic technique called exome sequencing, the team discovered a single coding error affecting a key residue in the CAMK2A gene that prevents its subunits from assembling correctly.

Moving their studies into the roundworm Caenorhabditis elegans, the scientists saw that this mutation disrupts the ability of CAMK2A to ensure proper neuronal communication and normal motor function. This suggests that the mutation is indeed the cause of the neurodevelopmental defects seen in the siblings.

To the best of the team’s knowledge, this new disorder represents the first human disease caused by inherited mutations on both copies of the CAMK2A gene. In addition, another report* published recently identified single-copy mutations on both CAMK2A and CAMK2B that caused intellectual disabilities as soon as the mutations occurred. “We would like to bring these findings to the attention of those working in the area of paediatric genetics, such as clinicians and genetic counsellors, as there are likely more undiagnosed children with similar symptoms who have mutations in their CAMK2A gene,” explains co-first author Franklin Zhong, Research Scientist in Reversade’s lab at A*STAR.

“Neuroscientists working to understand childhood brain development, neuronal function and memory formation also need to consider this new disease, since CAMK2A is associated with these processes. In future, it would be interesting to test whether restoring CAMK2A activity can bring therapeutic benefit to patients with this condition, as well as those with related neurological disorders.”

The paper ‘A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability‘ can be freely accessed online at https://doi.org/10.7554/eLife.32451. Contents, including text, figures and data, are free to reuse under a CC BY 4.0 license.

*Küry, S., van Woerden, G.M., Besnard, T., Proietti Onori, M., Latypova, X., Towne, M.C., Cho, M.T., Prescott, T.E., Ploeg, M.A., Sanders, S., et al. (2017). De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability. The American Journal of Human Genetics 101, 768-788.

https://www.technologynetworks.com/neuroscience/news/new-inherited-neurodevelopmental-disease-discovered-303233?utm_campaign=Newsletter_TN_BreakingScienceNews&utm_source=hs_email&utm_medium=email&utm_content=63149617&_hsenc=p2ANqtz-_AJri5fciUzcysqtDye56dm2VpMIbIwRqkV2di9BmqZhzk9xuPEv5CWgKF24BpT8_OB1uWAjitxNXhmduWHyW2XKGlhw&_hsmi=63149617

by Philip Perry

Researchers at the Salk Institute in La Jolla, California have discovered a way to turn back the hands of time. Juan Carlos Izpisua Belmonte led this study, published in the journal Cell. Here, elderly mice underwent a new sort of gene therapy for six weeks. Afterward, their injuries healed, their heart health improved, and even their spines were straighter. The mice also lived longer, 30% longer.

Today, we target individual age-related diseases when they spring up. But this study could help us develop a therapy to attack aging itself, and perhaps even target it before it begins taking shape. But such a therapy is at least ten years away, according to Izpisua Belmonte.

Many biologists now believe that the body, specifically the telomeres—the structures at the end of chromosomes, after a certain time simply wear out. Once degradation overtakes us, it’s the beginning of the end. This study strengthens another theory. Over the course of a cell’s life, epigenetic changes occur. This is the activation or depression of certain genes in order to allow the organism to respond better to its environment. Methylation tags are added to activate genes. These changes build up over time, slowing us down, and making us vulnerable to disease.


Chromosomes with telomeres in red.

Though we may add life to years, don’t consider immortality an option, at least not in the near-term. “There are probably still limits that we will face in terms of complete reversal of aging,” Izpisua Belmonte said. “Our focus is not only extension of lifespan but most importantly health-span.” That means adding more healthy years to life, a noble prospect indeed.

The technique employs induced pluripotent stem cells (iPS). These are similar to those which are present in developing embryos. They are important as they can turn into any type of cell in the body. The technique was first used to turn back time on human skin cells, successfully.

By switching around four essential genes, all active inside the womb, scientists were able to turn skin cells into iPS cells. These four genes are known as Yamanaka factors. Scientists have been aware of their potential in anti-aging medicine for some time. In the next leg, researchers used genetically engineered mice who could have their Yamanaka factors manipulated easily, once they were exposed to a certain agent, present in their drinking water.

Since Yamanaka factors reset genes to where they were before regulators came and changed them, researchers believe this strengthens the notion that aging is an accumulation of epigenetic changes. What’s really exciting is that this procedure alters the epigenome itself, rather than having the change the genes of each individual cell.


The mechanics of epigenetics.

In another leg of the experiment, mice with progeria underwent this therapy. Progeria is a disease that causes accelerated aging. Those who have seen children who look like seniors know the condition. It leads to organ damage and early death. But after six months of treatment, the mice looked younger. They had better muscle tone and younger looking skin, and even lived around 30% longer than those who did not undergo the treatment.

Luckily for the mice, time was turned back the appropriate amount. If turned back too far, stem cells can proliferate in an uncontrolled fashion, which could lead to tumor formation. This is why researchers have been reticent to activate the Yamanaka factors directly. However, these scientists figured out that by intermittently stimulating the factors, they could reverse the aging process, without causing cancer. The next decade will concentrate on perfecting this technique.

Since the threat of cancer is great, terminally ill patients would be the first to take part in a human trial, most likely those with progeria. Unfortunately, the method used in this study could not directly be applied to a fully functioning human. But researchers believe a drug could do the job, and they are actively developing one.

“This study shows that aging is a very dynamic and plastic process, and therefore will be more amenable to therapeutic interventions than what we previously thought,” Izpisua Belmonte said. Of course, mouse systems and human one’s are far different. This only gives us an indication of whether or not it might work. And even if it does, scientists will have to figure out how far to turn back the clock. But as Izpisua Belmonte said, “With careful modulation, aging might be reversed.”


Sixty trays can contain the entire human genome as 23,040 different fragments of cloned DNA. Credit James King-Holmes/Science Source

By ANDREW POLLACK

Scientists are now contemplating the fabrication of a human genome, meaning they would use chemicals to manufacture all the DNA contained in human chromosomes.

The prospect is spurring both intrigue and concern in the life sciences community because it might be possible, such as through cloning, to use a synthetic genome to create human beings without biological parents.

While the project is still in the idea phase, and also involves efforts to improve DNA synthesis in general.

Organizers said the project could have a big scientific payoff and would be a follow-up to the original Human Genome Project, which was aimed at reading the sequence of the three billion chemical letters in the DNA blueprint of human life. The new project, by contrast, would involve not reading, but rather writing the human genome — synthesizing all three billion units from chemicals.

But such an attempt would raise numerous ethical issues. Could scientists create humans with certain kinds of traits, perhaps people born and bred to be soldiers? Or might it be possible to make copies of specific people?

“Would it be O.K., for example, to sequence and then synthesize Einstein’s genome?” Drew Endy, a bioengineer at Stanford, and Laurie Zoloth, a bioethicist at Northwestern University, wrote in an essay criticizing the proposed project. “If so how many Einstein genomes should be made and installed in cells, and who would get to make them?”

The project was initially called HGP2: The Human Genome Synthesis Project, with HGP referring to the Human Genome Project. An invitation to the meeting at Harvard said that the primary goal “would be to synthesize a complete human genome in a cell line within a period of 10 years.”

But by the time the meeting was held, the name had been changed to “HGP-Write: Testing Large Synthetic Genomes in Cells.”

The project does not yet have funding, Dr. Church said, though various companies and foundations would be invited to contribute, and some have indicated interest. The federal government will also be asked. A spokeswoman for the National Institutes of Health declined to comment, saying the project was in too early a stage.

Besides Dr. Church, the organizers include Jef Boeke, director of the institute for systems genetics at NYU Langone Medical Center, and Andrew Hessel, a self-described futurist who works at the Bay Area software company Autodesk and who first proposed such a project in 2012.

Scientists and companies can now change the DNA in cells, for example, by adding foreign genes or changing the letters in the existing genes. This technique is routinely used to make drugs, such as insulin for diabetes, inside genetically modified cells, as well as to make genetically modified crops. And scientists are now debating the ethics of new technology that might allow genetic changes to be made in embryos.

But synthesizing a gene, or an entire genome, would provide the opportunity to make even more extensive changes in DNA.

For instance, companies are now using organisms like yeast to make complex chemicals, like flavorings and fragrances. That requires adding not just one gene to the yeast, like to make insulin, but numerous genes in order to create an entire chemical production process within the cell. With that much tinkering needed, it can be easier to synthesize the DNA from scratch.

Right now, synthesizing DNA is difficult and error-prone. Existing techniques can reliably make strands that are only about 200 base pairs long, with the base pairs being the chemical units in DNA. A single gene can be hundreds or thousands of base pairs long. To synthesize one of those, multiple 200-unit segments have to be spliced together.

But the cost and capabilities are rapidly improving. Dr. Endy of Stanford, who is a co-founder of a DNA synthesis company called Gen9, said the cost of synthesizing genes has plummeted from $4 per base pair in 2003 to 3 cents now. But even at that rate, the cost for three billion letters would be $90 million. He said if costs continued to decline at the same pace, that figure could reach $100,000 in 20 years.

J. Craig Venter, the genetic scientist, synthesized a bacterial genome consisting of about a million base pairs. The synthetic genome was inserted into a cell and took control of that cell. While his first synthetic genome was mainly a copy of an existing genome, Dr. Venter and colleagues this year synthesized a more original bacterial genome, about 500,000 base pairs long.

Dr. Boeke is leading an international consortium that is synthesizing the genome of yeast, which consists of about 12 million base pairs. The scientists are making changes, such as deleting stretches of DNA that do not have any function, in an attempt to make a more streamlined and stable genome.

But the human genome is more than 200 times as large as that of yeast and it is not clear if such a synthesis would be feasible.

Jeremy Minshull, chief executive of DNA2.0, a DNA synthesis company, questioned if the effort would be worth it.

“Our ability to understand what to build is so far behind what we can build,” said Dr. Minshull, who was invited to the meeting at Harvard but did not attend. “I just don’t think that being able to make more and more and more and cheaper and cheaper and cheaper is going to get us the understanding we need.”

By Marlene Cimons

Mary Harada’s father lived to 102, healthy and sharp to the end. She wouldn’t mind living that long, if she could stay as mentally and physically fit as he was. “He died sitting in his chair,’’ says Harada, 80, a retired history professor who lives in West Newbury, Mass. “He was in excellent shape until his heart stopped.’’

She may, in fact, have a good chance of getting there. Longevity experts believe that extreme old age — 100 or older — runs in families, and often is strikingly apparent in families where there are several siblings or other close relatives who have reached that milestone. (Harada’s great-aunt — her father’s aunt — also lived an extremely long life, to 104.)

Moreover, researchers are finding that many of those who live to extreme old age remain in remarkably good condition, delaying the onset of such chronic and debilitating age-related illnesses as cancer, heart disease and diabetes until close to the end of their lives, and a certain percentage don’t get them at all.

“It’s one thing to live to be 100 and quite another to live to be 100 and be in good shape,’’ says Winifred K. Rossi, deputy director of the Division of Geriatrics and Clinical Gerontology at the National Institute on Aging. The institute is sponsoring an ongoing study of more than 500 families with long-lived members that involves nearly 5,000 individuals. “Something is going on that has protected them from the bad stuff that causes problems for other people earlier in life.’’

Experts attribute healthy longevity to a combination of good genes and good behaviors. Good behaviors play a greater role than genes in getting you to your mid-to-late 80s — don’t smoke or drink alcohol, exercise regularly and eat healthfully — while getting beyond 90, and to 100 or even older, probably depends more heavily on genes, they say. Families with a cluster of members with exceptional longevity don’t occur by chance, they say, but probably from familial factors they all share.

Growing numbers

Centenarians have become a fast-growing group in this country. In 1980, there were 32,194 Americans age 100 or older. By 2010, the number had grown to 53,364, or 1.73 centenarians per 10,000 people, according to the Census Bureau. This represents a 65.8 percent increase during that period, compared with a 36.3 percent rise in the general population.

Moreover, the number of Americans 90 and older nearly tripled during the past three decades, reaching 1.9 million in 2010, and is expected to more than quadruple between 2010 and 2050, according to the bureau. Globally, the number of centenarians is expected to increase tenfold during that time, according to the aging institute.

This is probably due to numerous factors, among them improved health care, dietary changes and reduced rates of smoking.

“When I started practicing, it was rare to see someone of 100, but now it’s not that strange at all,’’ says Anne B. Newman, director of the Center for Healthy Aging at the University of Pittsburgh. “More people have had the opportunity to get there,’’ largely because of advances in public health and medicine.

But as the numbers of very old have increased and the examination of human genetics has become more sophisticated, researchers have been trying to discover the genetic and biological factors that contribute to a life span of 100 or older and why some centenarians stay healthy for so long. Not surprisingly, what they are finding is complicated and far from a one-size-fits-all answer.

“Aging is not simple,’’ says Thomas Perls, a professor of medicine at Boston University and director of the New England Centenarian Study at Boston Medical Center. “There are many different biological mechanisms involved in aging, so it makes sense that there are different genes involved. We are still in the infancy of figuring this out.’’

Nir Barzilai, director of the Institute for Aging Research at the Albert Einstein College of Medicine in New York, has been conducting several studies that focus on inherited genetic and biological influences that promote longevity.

In 2003, for example, his team discovered that centenarians, especially women, and their offspring have significantly higher HDL, or good cholesterol, which protects against heart disease, hypertension and metabolic syndrome, a series of risk factors that raise the chances of heart disease, diabetes and stroke.

Health & Science
Do you think you’ll live to be 100? The answer may be in your genes.
By Marlene Cimons December 14, 2015
Mary Harada’s father lived to 102, healthy and sharp to the end. She wouldn’t mind living that long, if she could stay as mentally and physically fit as he was. “He died sitting in his chair,’’ says Harada, 80, a retired history professor who lives in West Newbury, Mass. “He was in excellent shape until his heart stopped.’’

She may, in fact, have a good chance of getting there. Longevity experts believe that extreme old age — 100 or older — runs in families, and often is strikingly apparent in families where there are several siblings or other close relatives who have reached that milestone. (Harada’s great-aunt — her father’s aunt — also lived an extremely long life, to 104.)

Moreover, researchers are finding that many of those who live to extreme old age remain in remarkably good condition, delaying the onset of such chronic and debilitating age-related illnesses as cancer, heart disease and diabetes until close to the end of their lives, and a certain percentage don’t get them at all.

[Tech Titan’s Latest Project: Defying Death]

“It’s one thing to live to be 100 and quite another to live to be 100 and be in good shape,’’ says Winifred K. Rossi, deputy director of the Division of Geriatrics and Clinical Gerontology at the National Institute on Aging. The institute is sponsoring an ongoing study of more than 500 families with long-lived members that involves nearly 5,000 individuals. “Something is going on that has protected them from the bad stuff that causes problems for other people earlier in life.’’

( Martin Tognola for The Washington Post)
Experts attribute healthy longevity to a combination of good genes and good behaviors. Good behaviors play a greater role than genes in getting you to your mid-to-late 80s — don’t smoke or drink alcohol, exercise regularly and eat healthfully — while getting beyond 90, and to 100 or even older, probably depends more heavily on genes, they say. Families with a cluster of members with exceptional longevity don’t occur by chance, they say, but probably from familial factors they all share.

Growing numbers
Centenarians have become a fast-growing group in this country. In 1980, there were 32,194 Americans age 100 or older. By 2010, the number had grown to 53,364, or 1.73 centenarians per 10,000 people, according to the Census Bureau. This represents a 65.8 percent increase during that period, compared with a 36.3 percent rise in the general population.

Moreover, the number of Americans 90 and older nearly tripled during the past three decades, reaching 1.9 million in 2010, and is expected to more than quadruple between 2010 and 2050, according to the bureau. Globally, the number of centenarians is expected to increase tenfold during that time, according to the aging institute.

This is probably due to numerous factors, among them improved health care, dietary changes and reduced rates of smoking.

“When I started practicing, it was rare to see someone of 100, but now it’s not that strange at all,’’ says Anne B. Newman, director of the Center for Healthy Aging at the University of Pittsburgh. “More people have had the opportunity to get there,’’ largely because of advances in public health and medicine.

But as the numbers of very old have increased and the examination of human genetics has become more sophisticated, researchers have been trying to discover the genetic and biological factors that contribute to a life span of 100 or older and why some centenarians stay healthy for so long. Not surprisingly, what they are finding is complicated and far from a one-size-fits-all answer.

“Aging is not simple,’’ says Thomas Perls, a professor of medicine at Boston University and director of the New England Centenarian Study at Boston Medical Center. “There are many different biological mechanisms involved in aging, so it makes sense that there are different genes involved. We are still in the infancy of figuring this out.’’

The average American can expect to live for about 80 years. But that may change as scientists develop new ways to prolong human life. In this game, you will have access to seven promising tools. Play to learn more. Can you make it to 100 years or beyond? VIEW GRAPHIC
Nir Barzilai, director of the Institute for Aging Research at the Albert Einstein College of Medicine in New York, has been conducting several studies that focus on inherited genetic and biological influences that promote longevity.

In 2003, for example, his team discovered that centenarians, especially women, and their offspring have significantly higher HDL, or good cholesterol, which protects against heart disease, hypertension and metabolic syndrome, a series of risk factors that raise the chances of heart disease, diabetes and stroke.

The results, which found HDL levels of 60 and higher within this group — anything lower than 50 raises the risk of heart disease — suggest a heritable trait “that promotes healthy aging,’’ he says. This isn’t surprising, considering that women outlive men overall and — in 2010 — nearly 83 percent of centenarians were female, according to the Census Bureau.

Unusual chemistry

The Einstein researchers also have found that centenarians and their offspring often make unusually large amounts of a peptide (a short chain of amino acids) called humanin, which declines with age in most people and whose loss contributes to the development of Type 2 diabetes and Alzheimer’s disease. This may help explain why those who produce higher levels of humanin enjoy greater protection against those diseases and experience exceptionally long lives. For these individuals, humanin diminishes as they age, too, but the levels are much higher to start with than those of average people.

Barzilai believes the propensity for high levels of both HDL and humanin is heritable: “Offspring of centenarians have higher levels of humanin than their parents. Same with HDL. It declines with age, so it’s more apparent in the offspring.’’

Perls and his colleagues, in a study released almost four years ago, concluded there is no single common gene variant responsible for exceptional longevity. Rather, after examining about 280 gene variations, they discovered a series of gene combinations — nearly two dozen, in fact — that they believe contribute to long lives, “meaning there are different ways to get to these old ages,’’ Perls says. “It’s like playing the lottery. If you get all seven numbers, you’ll hit the jackpot.’’

These genetic groupings also seem to be involved in protecting against developing age-related diseases, since the scientists did not find an absence of disease-causing genes in their study group. “They have just as many as everybody else, which was a big surprise to us,’’ Perls says.

Also, the researchers found that the children of these healthy centenarians stay healthy longer than their same-age counterparts. The offspring of centenarians show 60 percent less heart disease, stroke, diabetes and hypertension, and 80 percent fewer overall deaths when they are in their early 70s, than those who were born at the same time but who do not have longevity in their families.

“They remain incredibly healthy into their 70s and 80s, and their mortality rate is very low, compared to others born at the same time,’’ Perls says.

Perls has studied 2,300 centenarians since 1995, including “super-centenarians’’ of 110 or older, and their offspring. He says about 45 percent of those who reach 100 manage to delay chronic age-related diseases until after they turn 80, and about 15 percent never get them at all.

Furthermore, he found that “semi-super-centenarians’’ — that is, those who are 105 to 109 — and super-centenarians don’t develop those diseases until roughly the final 5 percent of their very long lives. “They are dealing with diseases much better than the average person,’’ he says, who is more likely to develop these diseases in the 60s and 70s.

Many eventually die from the same diseases as non-centenarians, “but they do it 30 years later,’’ Barzilai says.

‘An additional 10 years’

Perls says that if you want to know whether you will live to 100, “you don’t have to do all this complicated genetic testing. Just look at your family and your health-related behaviors.’’ If you engage in healthful practices, you could reach your late 80s. “If you have the genes for longevity and you fight them [with risky behaviors], you will chop time off,’’ he says. “But if there is longevity in your family and you don’t do those things, you might get an additional 10 years past 90.’’

Newman agrees. “Don’t underestimate how powerful lifestyle is in longevity,’’ she says. “Even if longevity runs in your family, your life expectancy still will be more influenced by how you take care of yourself. If you have a centenarian parent, don’t count on living to 100 if you smoke, drink, eat a high-fat diet, and are sedentary and sleep-deprived.’’

Mary Harada thinks less about her genes and more about the unexpected event — breaking a bone, for example — that could make her a burden to her adult children.

“I don’t spend much time thinking about how long I’m going to live,’’ she says. “Whatever happens, happens. I spend more time thinking about how long I’m going to stay in my current house.’’

She has no age-related diseases and always has taken good care of herself. She has been a runner for 47 years, and she lifts weights. She shuns smoking and avoids most processed foods. She lives alone — her husband died last year — and she does most of the maintenance in and around her four-bedroom house, including leaf removal, routine yard work and spending two hours every 10 days in spring and summer mowing a very hilly lawn.

“I’ve lived here for 40 years, and I like living in this house and in this town,’’ she says. “If I could be like my father, and not break anything, I would stay here another five to 10 years. That would be wonderful.’’

https://www.washingtonpost.com/national/health-science/do-you-have-genes-that-will-let-you-live-to-age-100/2015/12/09/1460f234-953d-11e5-a2d6-f57908580b1f_story.html

Excessive activity in complement component 4 (C4) genes linked to the development of schizophrenia may explain the excessive pruning and reduced number of synapses in the brains of patients with schizophrenia, according to a study published in Nature.

The study, co-funded by the Office of Genomics Research Coordination at the National Institute of Mental Health and the Stanley Center for Psychiatric Research at the Broad Institute in Cambridge, Massachusetts, analyzed various structurally diverse versions of the C4 gene.

Led by Steve McCarroll, PhD, of the Broad Institute of Harvard and MIT, researchers analyzed the genomes of 65 000 study participants and 700 postmortem brains, detecting a link between specific gene versions and the biological process that causes some cases of schizophrenia.

The team—including Beth Stevens, PhD; Michael Carroll, PhD; and Aswin Sekar, BBS— determined that C4 genes generate varying levels of C4A and C4B proteins; the more C4A found in a person, the higher his or her risk of developing schizophrenia. The researchers found that during critical periods of brain maturation, C4 identifies synapses for pruning. Overexpression of C4 results in higher amounts of C4A, which could cause excessive pruning during the late teens and early adulthood, “conspicuously corresponding to the age-of-onset of schizophrenia symptoms,” the researchers noted.

“It has been virtually impossible to model [schizophrenic] disorder in cells or animals,” said Dr McCarroll. “The human genome is providing a powerful new way into this disease. Understanding these genetic effects on risk is a way of prying open that black box, peering inside, and starting to see actual biological mechanisms.”

Research suggests that future schizophrenia treatments may be developed to target and suppress excessive levels of pruning, halting a process that has the potential to develop into psychotic illness.

Reference

Sekar A, Bialas AR, de Rivera H, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016; doi: 10.1038/nature16549.