INDIANAPOLIS — The visible impacts of depression and stress that can be seen in a person's face — and contribute to shorter lives — can also be found in alterations in genetic activity, according to newly published research.

In a series of studies involving both C. elegans worms and human cohorts, researchers from the Indiana University School of Medicine and the Scripps Research Institute have identified a series of genes that may modulate the effects of good or bad mood and response to stress on lifespan. In particular, the research pointed to a gene known as ANK3 as playing a key role in affecting longevity. The research was published online May 24 in the Nature Publishing Group journal Molecular Psychiatry, the top ranked journal in the field of psychiatry.

"We were looking for genes that might be at the interface between mood, stress and longevity", said Alexander B. Niculescu III, M.D., Ph.D., professor of psychiatry and medical neuroscience at the IU School of Medicine. "We have found a series of genes involved in mood disorders and stress disorders which also seem to be involved in longevity.

"Our subsequent analyses of these genes found that they change in expression with age, and that people subject to significant stress and/or mood disorders, such as people who committed suicide, had a shift in expression levels of these genes that would be associated with premature aging and reduced longevity," said Dr. Niculescu, who is also attending psychiatrist and research and development investigator at the Indianapolis Veterans Affairs Medical Center.

The research began with studies in C. elegans, a worm widely used in life sciences research. An earlier study by one of the study co-authors, Michael Petrascheck, Ph.D., of the Scripps Research Institute, found that exposing C. elegans to the antidepressant mianserin, which is used to treat mood and stress disorders, extended the animal's lifespan.

In the Molecular Psychiatry study, the researchers methodically conducted a series of analyses to discover, prioritize, validate, and understand the genes involved, comprising ten steps:

  • In C. elegans, 231 genes were identified whose activities were altered after administration of mianserin and for which there were 347 similar genes in humans.
  • The 347 human genes were cross-referenced with a genome analysis of data from 3,577 older adults to identify those genes that might be associated with depressive symptoms in humans, resulting in 134 genes that overlapped.
  • The 134 genes were prioritized for involvement in mood disorders and stress disorders, using the Niculescu lab's Convergent Functional Genomics approach and comprehensive databases of human and animal model genetic and gene expression studies in psychiatric disorders. The top scoring gene from the list was ANK3, which in recent years has become well known as playing a role in psychiatric disorders.
  • Returning to the C. elegans model, the researchers tested the effects of mianserin and of oxidative stress on worms with mutated — and therefore inactive — versions of the ANK3 gene, compared to non-mutated wild-type worms. ANK3 expression increases with age in worms. Mianserin maintains lower, youthful levels of ANK3 expression, but does require some ANK3 to be present for its effects on longevity. Thus, there seems to be a “Goldilocks” effect.
  • Next, using more than 700 blood samples from patients diagnosed with psychiatric disorders, as well as studying samples from the Marion County (Indianapolis, Ind.) Coroner's office of people who had committed suicide, the investigators found significantly higher levels of expression of ANK3 in older (middle aged) patients than in younger patients, and a shift towards higher ANK3 levels in people who had committed suicide. Higher levels of ANK3 have also been reported independently by others in individuals with Hutchinson–Gilford progeria syndrome, a form of accelerated aging.
  • Adding genes that had scored nearly as high as ANK3 in the Convergent Functional Genomics analysis to create a panel of biomarkers showed similar but somewhat stronger results, particularly in people who had committed suicide.
  • Mitochondrial dysfunction was the top biological pathway where the top candidate genes for mood and stress-modulated longevity mapped. Over the last decade, accumulating evidence has suggested a causative link between mitochondrial dysfunction and aging.
  • A few of the genes identified in this study are changed in opposite direction in longevity compared to previous reports in Alzheimer Disease (AD), raising the possibility that the treatment of mood and stress disorders earlier in life might have an impact on later life AD.
  • A large number of top genes identified in this study were changed in opposite direction in longevity compared to patterns of expression in suicide revealed by previous studies from the Niculescu group, suggesting the possibility of an evolutionary organismal “life switch”, actively controlled by mood and stress.
  • Bioinformatics drug repurposing analyses revealed a series of compounds that may act on these genes and promote longevity, such as the relatively innocuous omega-3 fatty acid DHA (docosahexaenoic acid), piracetam, quercetin, vitamin D and resveratrol, along with a series of existing drugs, such as estrogen-like compounds, antidiabetics and rapamycin.

The authors said "these studies uncover ANK3 and other genes in our dataset as biological links between mood, stress and lifespan, that may be biomarkers for biological age as well as targets for personalized preventive or therapeutic interventions."

Additional information about Dr. Niculescu’s work is available at his laboratory website: www.neurophenomics.info.

Niculescu and colleagues disclosed this work to the Indiana University Research and Technology Corp and The Scripps Research Institute. IURTC and TSRI have applied for patent protection on the work.

Additional investigators contributing to the research were Sunitha Rangaraju, Daniel R. Salomon, and Michael Petrascheck, of the Scripps Research Institute; Daniel F. Levey, Kwangsik Nho, Nitika Jain, Katie Andrews, Helen Le-Niculescu, and Andrew J. Saykin, of the Indiana University School of Medicine.

The research was supported by two National Institutes of Health Directors’ New Innovator Awards (1DP2OD007363 and 1DP2OD008398), as well as NIH U19 A1063603, NIH R00 LM011384 and IADC P30 AG010133.

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FOR IMMEDIATE RELEASE

INDIANAPOLIS — Indiana University-Purdue University Indianapolis researchers in the School of Engineering and Technology, School of Medicine, and School of Science have received a total of $85,000 in FORCES funding to support the development and commercialization of their work.

The Office of the Vice Chancellor for Research oversees FORCES, or Funding Opportunities for Research Commercialization and Economic Success. The initiative has awarded more than $1 million to more than 30 faculty members since 2011.

Kevin Michael Berkopes, a mathematician in the School of Science and director of the Mathematics Assistance Center and Statistics Assistance Center, received $35,000 for "Virtual Learning Spaces: Creating Virtual Spaces for Future Teacher Support and Professional Exam Preparation." The work could support future mathematics and K-5 general-education teachers.

"This FORCES funding will help researchers from the School of Science and the School of Education collaborate to create high-tech virtual learning spaces," he said. "The intention is to create a virtual learning space that is embedded in the learning management system canvas and available free of charge to all IUPUI students enrolled in the elementary-education degree path."

Berkopes founded Crossroads Education through the Spin Up program of the Indiana University Research and Technology Corp. to commercialize his work.

"Should the product prove impactful, we intend to apply for funding to investigate our virtual learning space design as something that is exportable to different sectors. We hope that we can research and investigate new technologies for providing quality interactions with mathematical content and to enable collaboration and professional development for current and future teachers of mathematics," he said.

Dr. Elliot J. Androphy, the Kampen-Norins Professor and chair of the Department of Dermatology at the School of Medicine, received $25,000 for "Evaluation of Novel Compounds for Motor Neuron Disease." The project will determine whether novel drug-like compounds being developed have activity in a human neurologic disease.

"The funding will allow us to purchase the mouse model of this disease, hire staff and perform experiments," he said. "If successful, we will apply for additional grants to characterize the mechanism by which these drugs act. It could be advanced into a clinical trial for people afflicted with neurologic disease."

Andres Tovar, assistant professor in the School of Engineering and Technology, received $25,000 for "Commercialization of a Topology Optimization Algorithm to Design Lightweight, Multi-Functional Components with Optimized Internal Cellular (Porous) Structure." The project could provide engineering product designers with a tool that automatically synthesizes porous architectures.

"The FORCES funding will facilitate the commercialization of this design algorithm, which was disclosed to IURTC in 2014. The algorithm has also been developed from existing research sponsored by Honda R&D America and the Walmart Foundation," he said. "The FORCES funding will support the development of an alpha version of the algorithm to make the design tool marketable."

The next round of applications for FORCES funding are due Sept. 15. Contact Karen White, 317-274-1083, kfwhite@iupui.edu, for information.

About Indiana University Research and Technology Corp.

IURTC is a not-for-profit corporation tasked with the protecting and commercializing of technology emanating from innovations by IU researchers. Since 1997, IU research has generated more than 2,700 inventions resulting in over 3,900 global patent applications being filed by IURTC. These discoveries have generated $133 million in licensing and royalty income, including $111 million in funding for IU departments, labs and inventors.​

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INDIANAPOLIS — The hard work put in by 418 future physicians and scientists will be recognized Saturday when the IU School of Medicine holds its annual commencement ceremonies at 10 a.m. in the Sagamore Ballroom of the Indiana Convention Center.

The keynote speaker this year will be Aaron Carroll, M.D., professor of pediatrics and associate dean for research mentoring at the IU School of Medicine. Dr. Carroll’s remarks will focus on preparing students for residency, his writings on depression among physicians, and why being a physician is a great career choice. Dr. Carroll has gained a national audience for his commentaries on health, medicine and policy issues in the Upshot section of the New York Times and numerous other publications, the Incidental Economist blog and the online video health program Healthcare Triage.

The IU School of Medicine will award:

  • 321 Doctor of Medicine degrees, including four M.D./Ph.D. and one M.D./MBA combined degrees
  • 33 Doctor of Philosophy degrees
  • 64 Master of Science degrees

A special segment of the ceremony is reserved for the newly named physicians. Following the formal hooding ceremony, IU School of Medicine Dean Jay L. Hess, M.D., Ph.D., M.H.S.A., will lead the new doctors in reciting the time-honored Physician’s Oath, promising, among other things, to practice their profession “with conscience and dignity” and always considering the health of their patients first and foremost.

In a ceremony Sunday afternoon, 144 associate and bachelor's degree graduates of the school's Health Professions Program will be recognized. The program includes emergency medical services, clinical laboratory science, cytotechnology, histotechnology, medical imaging technology, nuclear medicine technology, paramedic science, radiation therapy, radiography and respiratory therapy.

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INDIANAPOLIS — Use of hospice services does not increase care costs in the last six months of life for long-stay nursing homes residents according to an analysis conducted by researchers from the Indiana University Center for Aging Research and the Regenstrief Institute.

Avoidance of costly hospitalization and subsequent post-acute care in the nursing home appears to offset hospice services costs, even when hospice services are provided over a prolonged period of time according to the study of 2,510 long stay nursing home decedents, a third of whom received hospice services. Age, race or gender had no effect on the findings.

"Effect of Hospice Use on Costs of Care for Long Stay Nursing Home Decedents" is published online ahead of print in the Journal of the American Geriatrics Society.

"The government, through Medicare and Medicaid, spends a lot of money on this vulnerable population, but is it getting appropriate value?," queries Indiana University Center for Aging Research and Regenstrief Institute investigator Kathleen Unroe, M.D., MHA, who led the study. "High quality end-of-life care for those living in nursing homes is the goal.

"An active debate about length of stay, reimbursement and other aspects of Medicare and Medicaid payment reform is underway. Our study provides data relevant to the evolving policy landscape surrounding hospice care." Dr. Unroe is an assistant professor of medicine at the IU School of Medicine.

Hospice is a service, not a place. Hospice care can and does take place in nursing homes with specially trained hospice workers coming to the facility to provide palliative care to terminal residents who have elected, or whose families have elected, hospice care which focuses on end-of-life comfort rather than cure.

"Hospice care is not always a perfect fit in nursing homes – it can be difficult to determine when a person with advanced dementia, for example, has truly reached the end of life," said Dr. Unroe. "But despite concerns that Medicare's hospice benefit is not being used appropriately in nursing homes, we didn't find evidence of cost shifting between Medicare and Medicaid."

The study found few significant differences in clinical or demographic characteristics between long stay nursing home decedents who did and did not receive hospice services near the end of life. The exception was residents with a cancer diagnosis, who were more likely to receive hospice than those with other diagnoses, also true of hospice use by those not in nursing homes. Advanced dementia also was associated with increased hospice use.

The long stay nursing home residents whose records were reviewed for this study were disproportionately poor, non-white and characterized by high health care costs — individuals often not included in healthcare utilization studies.

In addition to Dr. Unroe, co-authors of the study are Greg Sachs, M.D., of the IU Center for Aging Research, Regenstrief Institute and IU School of Medicine; M.E. Dennis, B.A., of the IU Center for Aging Research and Regenstrief Institute; Susan Hickman, Ph.D., of the IU School of Nursing; Timothy Stump, M.A., of the Regenstrief Institute; Wanzhu Tu, Ph.D. and Christopher Callahan, M.D., of the IU Center for Aging Research, the Regenstrief Institute and IU School of Medicine. Dr. Sachs is division director of the IU School of Medicine's Division of General Medicine and Geriatrics. Dr. Callahan is founding director of the IU Center for Aging Research.

In 2014 the authors published a study in the Journal of General Internal Medicine comparing the characteristics of hospice patients in nursing homes with hospice patients living in the community.

Both studies were funded by National Palliative Care Research Center Grant 4183655 and National Institute on Aging Grants R01 AG031222 and K24 AG024078.

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