Psychologist Darby Saxbe leads the Center for the Changing Family and a research effort to explore how parents change biologicially and neurobiologically in response to their babies — all at the USC Dornsife College of Letters, Arts and Sciences.

Saxbe, an associate professor, recently had a study published in the journal Cerebral Cortex and found evidence that men develop a sort of “dad brain” after their baby is born, somewhat like how mothers’ brains change in response to their newborns. She discussed why studying these changes in parents is important and what she hopes to tackle next.

Why are you studying these changes in the parents’ brains? What do you hope to understand?

Parenting is incredibly important for society and public health, but also understudied from a neurobiological perspective. We’re hoping our research can inform public policies like paid family leave and other initiatives that support new parents.

What is neuroplasticity and what does it usually signify? Why would it change when one becomes a parent?

We’re still learning about neuroplasticity, but there is evidence that the brain changes and grows when we develop a new skill, like learning a musical instrument, or during developmental windows like early childhood and adolescence. Becoming a parent entails changes to your lifestyle and your biology and requires new skills like being able to empathize with a nonverbal infant, so it makes sense — but has not been proven — that the brain would be particularly plastic during the transition to parenthood as well.

What is the “parental caregiving brain network”? Does this exist for mothers, too?

Yes — it does exist for mothers — this refers to areas of the brain that have been shown to be involved in parenting or caregiving (and pregnancy and lactation) in both human and animal studies.

The study shows that you found changes in the default mode network. What is this network and what do these changes mean for men who are new fathers? What does it mean for their partners?

The default mode network refers to the regions of the brain that “light up” when the brain is at rest (not doing a particularly cognitive task). These regions are thought to be involved in mentalizing about other people’s thoughts and feelings. The fact that we found changes in that part of the brain both for fathers and mothers suggests that there is some remodeling of the social brain taking place.

You note that these changes are occurring in the cortex. What is the cortex responsible for, particularly as it relates to parenting?

The cortex is the latest-evolving part of the brain that is involved in attention, planning, and executive functioning and is more unique to humans. The subcortical regions (below the cortex) are the more basic brain structures that you see in animals, involved in reward, threat, and salience detection. In moms we see both subcortical and cortical changes … in dads we just saw cortical changes. It’s too soon to speculate with such a small sample but it might suggest more higher-order processing involved in fatherhood specifically.

Noted in here, too, is that volumes in the men’s visual network decreased. Do you have any hypotheses on the reasons that would drive changes in the visual system?

We’re not sure, although it may be that visual cues are particularly important for orienting to offspring and understanding their needs, given that infants are non-verbal.

Based on your results, what do you want to explore next?

We plan to study individual differences in fathers’ brain changes that are associated with hormones and parenting.

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A USC-led team of scientists has found indications that a special blood test called a liquid biopsy could determine whether a patient has breast cancer at its early stage and if that cancer is unlikely to return.

The high-definition comprehensive liquid biopsies are conducted using a standard blood draw from the arm of a patient in a doctor’s office. Once in the laboratory, the sample is examined for signs of cancer.

The study demonstrating the liquid biopsy results for early breast cancer detection was published on Sept. 27 in Nature’s npj Breast Cancer journal. The work was a collaboration between USC, Billings Clinic, Duke University, Epic Sciences and the USC Norris Comprehensive Cancer Center. The results raise hopes that one day doctors could detect breast cancer in patients with a simple blood draw.

The researchers at the USC Michelson Convergent Science Institute in Cancer (CSI-Cancer) are cautiously optimistic about their findings. They are eager to test and see whether the results will be proven in larger clinical trials to demonstrate the benefit of the method for patients everywhere.

It’s an amazing opportunity to change how early breast cancer detection is being done with a simple blood draw.

Peter Kuhn, USC’s CSI-Cancer

“It’s an amazing opportunity to change how early breast cancer detection is being done with a simple blood draw, but it’s only a research outcome at this point and we still need to demonstrate clinical benefit,” said Peter Kuhn, a USC cancer physicist who directs CSI-Cancer.

Breast cancer is the most prevalent form of cancer in the world, affecting 1 in 8 women over their lifetime.

Since 1976 when the American Cancer Society endorsed mammography X-rays, the technique — along with a tissue biopsy — has become the standard way for doctors to check patients for breast cancer.

Breast cancer detection: Mammography isn’t 100% accurate

But mammography is not 100% accurate and its detection can be impeded by healthy dense tissue. Mammography’s sensitivity to breast cancer is about 87%, according to the Breast Cancer Surveillance Consortium. And for some women, mammograms are not accessible, especially those living in poor isolated communities that have no clinics or hospitals. Other women simply do not get a regular mammogram.

But a tissue biopsy also is not a foolproof method. Although it can reveal information about the tumor, it has limitations. Doctors can sample only a small area and may fail to capture the full extent of the tumor. A tissue biopsy is also invasive and painful.

Combined, the drawbacks for diagnosis with mammograms and tissue biopsies mean some patients are not diagnosed until the cancer has grown and spread. New methodologies such as CSI-Cancer’s liquid biopsy can bring a complementary toolset into clinical practice.

For the study, Kuhn and his team worked with 100 breast cancer patients — some early and some late stage — and 40 patients without breast cancer from April 2013 through January 2017. The work was conducted at clinical sites including at the USC Norris cancer center at the Keck School of Medicine of USC; the Billings Clinic in Montana; the Duke University Cancer Institute in Durham, N.C.; and the City of Hope Comprehensive Cancer Center in Duarte.

The team tested a theory that the high-definition liquid biopsy could detect multiple cancer biomarkers, including the so-called “oncosomes” — nano-sized, membraned cargo carriers that enrich the body’s environment for cancer growth. These oncosomes are secreted by cancer cells as the group has shown previously.

“The news here is that we found the vast majority of early-stage breast cancer patients have these oncosomes at very robust levels,” said Kuhn, a Dean’s Professor at the USC Dornsife College of Letters, Arts and Sciences and cancer physicist. “They’re about 5-10 microns in diameter, about the size of a cell. We first identified these large vesicles in prostate cancer about a year-and-a-half ago and showed that they are related to the cancer. They are hiding in plain sight.”

A future diagnostic tool for breast cancer detection?

If further studies produce similar results, it could mean that the next generation high-definition liquid biopsy may become a diagnostic tool for early breast cancer detection and other cancers, he said. The test also could inform patients who have been treated for cancer that they will most likely remain cancer-free.

“Typically, I’m the bearer of bad news. I say, ‘You have cancer in your blood,'” Kuhn said. “But a test like this could give hope that if there is a sign of cancer, we can find it very early and improve treatment and survival.”

Kuhn’s co-authors included from USC: Sonia Maryam Setayesh, Olivia Hart, Amin Naghdloo and Nikki Higa, Anand Kolatkar, as well as Nicholas Matsumoto, Rafael Nevarez, James B. Hicks, Jeremy Mason, Stephanie N. Shishido at USC Michelson. Other researchers were Jorge Nieva and Janice Lu of the USC Norris Center at Keck Medicine of USC, Shelley Hwang of Duke University School of Medicine, Kathy Wilkinson and Michael Kidd of Billings Clinic, as well as Amanda Anderson of Epic Sciences in San Diego.

The study was funded by grants from Breast Cancer Research Foundation; USC Norris Comprehensive Cancer Center; the National Cancer Institute; National Institutes of Health; Kalayil and Leela Chacko, Fellowship; Winnie and James Hart Endowed Fellowship; USC Dornsife Student Opportunities for Academic Research Fellowship; Vassiliadis Research Fund; Vicky Joseph Research Fund; Hart Family Research Fund; The Hsieh Family Foundation; Sandy Borden Thielicke; Jennifer B. and Gregory A. Ezring; Rochika and Kenny Dewan; Andy Perlman; Neil and Anjini Desai; Mamak and Mahmood Razavi Research Fund; Susan Pekarovics; Anila P. Bhagavatula; Giorgio De Santis; Thuy Thanh Truong; Cheryl Faillace; Wayne R. Green Fund; Armstrong McDonald Foundation; Ms. Margaret Turney Hulter Funds; Suzanne B. Borden Fund; and Mr. and Mrs. Stanley A. Mayer Fund.

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Fasting-Mimicking Diet Reduces Signs of Dementia in Mice

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Fasting-Mimicking Diet Reduces Signs of Dementia in Mice

Short cycles of a low-calorie diet that replicates fasting appeared to reduce inflammation and delay cognitive decline in mouse models of Alzheimer’s disease; initial data indicates diet’s safety in Alzheimer’s patients.
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Cycles of a diet that mimics fasting appear to reduce signs of Alzheimer’s in mice genetically engineered to develop the illness, according to a new USC Leonard Davis School of Gerontology-led study.

The study appeared in Cell Reports on Sept. 27.

The researchers, led by Professor Valter Longo in collaboration with Professors Christian Pike and Pinchas Cohen, found that mice that had undergone several cycles of the fasting-mimicking diet showed less Alzheimer’s pathology. The researchers found lower levels of two major hallmarks of the disease: amyloid beta – the primary driver of plaque buildup in the brain – and hyperphosphorylated tau protein, which forms tangles in the brain. They also found that brain inflammation lessened and better performance on cognitive tests compared to the mice that were fed a standard diet.

The fasting-mimicking diet (FMD) is high in unsaturated fats and low in overall calories, protein, and carbohydrates and is designed to mimic the effects of a water-only fast while still providing necessary nutrients. Previous research led by Longo has indicated that brief, periodic FMD cycles are associated with a range of beneficial effects, including the promotion of stem cell regeneration, lessening of chemotherapy side effects, and lowering risk factors for cancer, diabetes, heart disease and other age-related diseases in mice and humans.

Promising results in mouse models of Alzheimer’s
Alongside healthy mice, the team investigated two mouse models of Alzheimer’s, E4FAD and 3xTg. During the study, mice were fed the fasting-mimicking diet for 4 or 5 days twice per month and were allowed to eat normally between FMD cycles. In a long-term experiment to see the effects in aged mice, 3xTg mice were placed on the diet for 30 cycles in 15 months. Shorter-term experiments in both 3xTg and E4FAD mice ranged from a single FMD cycle to 12 cycles in 6 months.

In both models, mice who underwent FMD cycles showed promising reductions in amyloid beta – which form the sticky, disruptive plaques in the brain – and tau pathology compared to mice eating a standard diet. The FMD mice also showed lower levels of brain inflammation, including a reduction in the number of active microglia, the immune cells that seek and destroy pathogens and damaged cells in the brain. In addition, mice on the diet demonstrated a lower level of oxidative stress, which plays a role in Alzheimer’s pathology by damaging neurons and contributing to the accumulation of amyloid in the brain. The study specifically pointed to the free radical “superoxide” as a central culprit in the damage occurring in these Alzheimer’s mouse models, Longo explained.

Outwardly, mice of both Alzheimer’s models who underwent the FMD showed less cognitive decline than their standard diet counterparts. Cognitive behavior, including exploration and performance within mazes, was tested in young mice before the dietary regimen began and again after several months of either a standard diet or twice-monthly FMD cycles. The Alzheimer’s mice given the FMD significantly outperformed the Alzheimer’s mice given standard diets and in some instances performed similarly to the non-Alzheimer’s-prone control mice, indicating that cognitive decline had been significantly slowed.

The FMD cycles appeared effective in reversing a range of pathology markers but also cognitive defects in two of the major mouse models for Alzheimer’s disease. Longo said that the results are promising.

Small clinical study explores feasibility for humans
In addition to the study in mice, Longo and colleagues also included data from a small Phase 1 clinical trial of the fasting-mimicking diet in human patients diagnosed with mild cognitive impairment or mild Alzheimer’s disease. Forty such patients who were otherwise healthy and had family support were randomized to either a once-monthly, 5-day fasting-mimicking diet or a 5-day period in which lunch or dinner was replaced with a meal based on pasta or rice.

Initial data indicates that the FMD is safe and feasible for patients with mild impairment or early Alzheimer’s disease. Further tests in the ongoing clinical trial will measure cognitive performance, inflammation and more, Longo said.

Other early trials of the diet published by Longo and colleagues have indicated other benefits of a monthly cycle, such as a loss of fat mass without loss of muscle mass and improved cardiometabolic risk factors, especially in overweight or obese people.

Notably, in a recently published clinical trial in which Longo was a co-author, FMD cycles were associated with disease regression in diabetes patients. Diabetes nearly doubles the risk of developing Alzheimer’s disease, per the Alzheimer’s Association.

Other authors included co-first authors Priya Rangan, Fleur Lobo and Edoardo Parrella of USC; Terri-Leigh Stephen, Christian J. Pike, Pinchas Cohen, Kyle Xia, Katelynn Tran, Brandon Ann, and Dolly Chowdhury of USC; Anna Laura Cremonini, Luca Tagliafico, Angelica Persia, Irene Caffa, Fiammetta Monacelli, Patrizio Odetti, Tommaso Bonfiglio, and Alessio Nencioni of the University of Genoa, Italy; Nicolas Rochette, Marco Morselli, and Matteo Pellegrini of UCLA; Mary Jo LaDu of the University of Illinois at Chicago; and Martina Pigliautile, Virginia Boccardi, and Patrizia Mecocci of the University of Perugia, Italy.

The study was funded in part by National Institutes of Health/National Institute on Aging grants AG20642, AG025135, and P01 AG034906 to Longo; AG058068 to Pike; the NIA T32 training grant AG052374 to Rangan; and the PE-2016-02362694 and PE-2016-02363073 grants by the Italian Ministry of Health to Odetti, Mecocci, Monacelli, and Longo. The LaDu lab is funded by NIH (NIA) R01 AG056472, R01 AG057008, UH2/3 NS10012, R56 AG058655, 1R44 AG060826, institutional funds from the College of Medicine at the University of Illinois, Chicago, and generous philanthropic contributions.

Longo is the founder of and has an ownership interest in L-Nutra; the company’s food products are used in studies of the fasting-mimicking diet. Longo’s interest in L-Nutra was disclosed and managed per USC’s conflict-of-interest policies. USC has an ownership interest in L-Nutra and the potential to receive royalty payments from L-Nutra. USC’s financial interest in the company has been disclosed and managed under USC’s institutional conflict-of-interest policies.

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REDIRECT 7902 Christian Hetrick
Author’s Email chetrick@usc.edu
Author’s Department
Price Office of Communication
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No
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https://priceschool.usc.edu/news/price-study-disadvantaged-workers-face-more-challenges-come-retirement/
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Study: Disadvantaged workers face more challenges come retirement
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As Healthy Aging Month comes to a close, research from Price School associate professor Emma Aguila documents the varied work pathways of America’s increasingly diverse older workforce.

Highlights:

? Workers with limited job opportunities face more obstacles in retirement – perpetuating inequities among demographic groups
? Various disparities, along with other inequities such as health and education, perpetuate income inequality come retirement
? Employer-sponsored pension plans cover about two-thirds of white workers, but just over one-third of Latino workers

American workers with limited job opportunities during their working years face obstacles in retirement too, perpetuating inequities among demographic groups. That’s according to research conducted by Emma Aguila, a USC Price School associate professor and expert on the economics of aging.

Aguila’s research, which was reported in a recent study for the National Academy of Sciences, Engineering and Medicine, sheds light on some of the challenges many older Americans face in planning for retirement or seeking to work longer into their lives.

As Healthy Aging Month comes to a close, the study documents the varied work pathways of America’s increasingly diverse older workforce. Disadvantaged older workers are more likely to be forced into involuntary retirement due to job loss or disability, for example. They may take on informal gigs that don’t contribute to the Social Security system, such as nannying. Hispanic and Black Americans in mid-skilled jobs have been particularly affected by automation, as well.

Additionally, historically disadvantaged groups are less likely to have control over where, when and how much they work at older ages.

Despite the growing diversity of the aging workforce, much of the existing research on older workers has focused on the experiences of economically and socially advantaged groups, the study concluded.

“I think we’ve been analyzing the population as if they all behave the same, like they all have full-time jobs and they follow this career path and then they retire,” Aguila said. “But I think what we really need to consider is the heterogeneity across the population.”

Take pensions, for example. Employer-sponsored plans covered about two-thirds (64.6%) of non-Hispanic white workers, 55.7% of Black workers, and just over one-third (38.4%) of Hispanic workers, Aguila reported.

Occupational segregation

Those differences can be explained in large part by occupational segregation. Whites are more likely to work at larger firms that provide pensions, while Blacks are more likely employed in the public sector, which often offers pensions, too. Hispanics, by contrast, are more likely to work at smaller firms or part time – jobs that are less likely to include employer-sponsored retirement plans.

Disparities like this, along with other inequities such as health and education, further perpetuate income inequality come retirement. “The more advantaged workers, they not only have Social Security, but they will have other sources of income” like savings or pensions, Aguila noted. “So the inequality continues.”

The National Academy tapped Aguila to analyze existing data and research on vulnerable older workers, as part of a broader report published in May examining the aging American workforce. She reported that there is not enough literature on the experience of these populations, limiting insight into how inequality in retirement and work opportunities affects older adults.

Aguila recommended that future research take a “life course perspective” on inequity in work and retirement. Gathering such data would require following people over time to better understand inequalities in later adulthood. Doing so is necessary because the causes of unequal work and retirement pathways begin long before age 50, she explained.

Pandemic effect
Aguila conducted her research just as the COVID-19 pandemic swept the country, putting older adults at heightened risk of serious illness or death, while prompting employers to lay off workers or send them home to work remotely. In many ways, the pandemic and the ensuing turmoil in the job market underscore the issues Aguila studied.

Still, she said it’s too early to know whether the pandemic exacerbated the problems she highlighted in her study.

“More research will come out,” Aguila said of the pandemic’s impact on older workers. “We will be able to understand better whether these issues were exacerbated.”

The post Disadvantaged workers face more challenges in retirement, too appeared first on USC News.

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https://gero.usc.edu/2022/09/20/alzheimer-risk-mitochondria-protein (will not be live until embargo lift)

EMBARGOED TO 5 PM TUE 9/20 PACIFIC TIME (1 AM BST WED 9/21)
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NEWLY DISCOVERED PROTEIN CONNECTED TO ALZHEIMER’S DISEASE RISK

A mutation in the small protein SHMOOSE is associated with Alzheimer’s risk and highlights a possible target for treatment.
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A mutation in a newly discovered small protein is connected to a significant increase in the risk for Alzheimer’s disease, expanding the known gene targets for the disease and presenting a new potential avenue for treatment, according to a new USC Leonard Davis School of Gerontology study.

The protein, called SHMOOSE, is a tiny “microprotein” encoded by a newly discovered gene within the cell’s energy-producing mitochondria. A mutation within this gene partially inactivates the SHMOOSE microprotein and is associated with a 20-50 % higher risk for Alzheimer’s disease across four different cohorts. Nearly a quarter of people of European ancestry have the mutated version of the protein, according to the researchers.

The research appears Wednesday, September 21 in the journal Molecular Psychiatry.

The researchers say that both the substantial risk and high prevalence of this previously unidentified mutation differentiate it from other proteins involved in Alzheimer’s disease. Apart from APOE4 — the most potent known genetic risk factor for the disease — only a limited number of other gene mutations have been identified and these only mildly increased risk by less than 10%. Also, because the microprotein is approximately the size of the insulin peptide, it can be easily administered, which increases its therapeutic potential.

“This discovery opens exciting new directions for developing precision medicine-based therapies for Alzheimer’s disease, focusing on SHMOOSE as a target area,” said Pinchas Cohen, professor of gerontology, medicine and biological sciences and senior author of the study. “Administration of SHMOOSE analogs in individuals who carry the mutation and produce the mutant protein may prove to have benefit in neurodegenerative and other diseases of aging.”

Brendan Miller, ’22 PhD in neuroscience graduate and first author of the study, used big data techniques to identify genetic variations in mitochondrial DNA associated with disease risk. After analyses revealed a gene mutation increased Alzheimer’s disease risk, brain atrophy, and energy metabolism, Miller and his colleagues discovered that the mutated gene coded for the SHMOOSE microprotein and began studying its mutated and default forms. The researchers stated SHMOOSE is the first mitochondrial-DNA-encoded microprotein to have been detected using both antibodies and mass spectrometry.

The microprotein appears to modify energy signaling and metabolism in the central nervous system. It was found in mitochondria of neurons and its levels in cerebrospinal fluid correlated with biomarkers of Alzheimer’s disease. A variety of cell culture and animal experiments showed that SHMOOSE alters energy metabolism in the brain in part by inhabiting a crucial part of the mitochondria, the inner mitochondrial membrane.

An emerging field of study

Miller said the findings highlights the importance of the relatively new field of microproteins. For decades, scientists have studied biology mostly by considering a set of 20,000 large protein-coding genes. However, new technology has highlighted hundreds of thousands of potential genes that encode smaller microproteins.

“The field of microproteins is still so new,” Miller said. “We don’t yet know how many microprotein genes are even functional, and the cost to study a potential microprotein one-by-one from a list of thousands is just too expensive and inefficient. The approach my colleagues and I used to detect SHMOOSE shows the power of integrating big genetics data with molecular and biochemical techniques to discover functional microproteins.”

USC Leonard Davis researchers are leaders in the study of microproteins, especially those coded within the mitochondrial genome. In 2003, Cohen and his colleagues were one of the three research teams to independently discover the protein humanin, which appears to have protective health effects in Alzheimer’s, atherosclerosis and diabetes. In the past few years, the Cohen Laboratory discovered several other mitochondrial microproteins, including, small humanin-like peptides, or SHLPs, and a microprotein called MOTS-c, an exercise-mimetic peptide that has entered clinical trials for obesity and fatty liver.

Additional coauthors include Su-Jeong Kim, Hemal H. Mehta, Kevin Cao, Hiroshi Kumagai, Neehar Thumaty, Naphada Leelaprachakul, Henry Jiao, Thalida E. Arpawong, Eileen Crimmins, Meral A. Tubi, Evan T. Hare, Meredith N. Braskie, Lea Decarie-Spain, Scott E. Kanoski, Lu Zhao, Arthur W. Toga, Junxiang Wan, and Kelvin Yen of USC; as well as Joan Vaughan, Jolene Diedrich, and Alan Saghatelian of the Salk Institute for Biological Studies; Nilufer Ertekin-Taner of the Mayo Clinic; and Francine Grodstein and David A. Bennett of the Rush University Medical Center.

The study was supported by NIH grants P30AG10161, P30AG072975, R01AG15819, R01AG17917, U01AG61356, R01AG069698, RF1AG061834, R01AG068405, P30AG068345, P01AG055369, DK118402, F31 AG059356, and T32 AG00037; as well as The Quebec Research Funds Postdoctoral Fellowship. Intellectual property related to SHMOOSE has been filed by the University of Southern California.

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