News

September 05, 2018

Mitochondrial DNA m.3243A>G heteroplasmy affects multiple aging phenotypes and risk of mortality

Gregory J. Tranah, Shana M. Katzman, Kevin Lauterjung, Kristine Yaffe, Todd M. Manini, Stephen Kritchevsky, Anne B. Newman, Tamara B. Harris, Steven R. Cummings

Abstract

Mitochondria contain many copies of a circular DNA molecule (mtDNA), which has been observed as a mixture of normal and mutated states known as heteroplasmy. Elevated heteroplasmy at a single mtDNA site, m.3243A > G, leads to neurologic, sensory, movement, metabolic, and cardiopulmonary impairments. We measured leukocyte mtDNA m.3243A > G heteroplasmy in 789 elderly men and women from the bi-racial, population-based Health, Aging, and Body Composition Study to identify associations with age-related functioning and mortality. Mutation burden for the m.3243A > G ranged from 0–19% and elevated heteroplasmy was associated with reduced strength, cognitive, metabolic, and cardiovascular functioning. Risk of all-cause, dementia and stroke mortality was significantly elevated for participants in the highest tertiles of m.3243A > G heteroplasmy. These results indicate that the accumulation of a rare genetic disease mutation, m.3243A > G, manifests as several aging outcomes and that some diseases of aging may be attributed

Free Paperhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082898/

Mitochondrial DNA m.13514G>A heteroplasmy is associated with depressive symptoms in the elderly

Gregory J. Tranah, Jeanne E. Maglione, Kristine Yaffe, Shana M. Katzman, Todd M. Manini, Stephen Kritchevsky, Anne B. Newman, Tamara B. Harris, Steven R. Cummings for the Health, Aging and Body Composition Study

 

Corresponding Author

E-mail address:gtranah@sfcc‐cpmc.netE-mail address:gtranah@psg.ucsf.eduLA Eye Center and Clinic, Los Angeles, CA, USAAbstract

Mitochondrial DNA (mtDNA) heteroplasmy is a mixture of normal and mutated mtDNA molecules in a cell. High levels of heteroplasmy at several mtDNA sites in complex I lead to inherited neurological neurologic diseases and brain magnetic resonance imaging (MRI) abnormalities. Here, we test the hypothesis that mtDNA heteroplasmy at these complex I sites is associated with depressive symptoms in the elderly.

We examined platelet mtDNA heteroplasmy for associations with depressive symptoms among 137 participants over age 70 from the community-based Health, Aging and Body Composition Study. Depressive symptoms were assessed using the 10-point version of the Center for Epidemiologic Studies Depression Scale (CES-D 10). Complete mtDNA sequencing was performed and heteroplasmy derived for 5 mtDNA sites associated with neurologic mitochondrial diseases and tested for associations with depressive symptoms.

Of 5 candidate complex I mtDNA mutations examined for effects on depressive symptoms, increased heteroplasmy at m.13514A>G, ND5, was significantly associated with higher CES-D score (P = .01). A statistically significant interaction between m.13514A > G heteroplasmy and sex was detected (P = .04); in sex-stratified analyses, the impact of m.13514A>G heteroplasmy was stronger in male (P = .003) than in female (P = .98) participants. Men in highest tertile of mtDNA heteroplasmy exhibited significantly higher (P = .0001) mean ± SE CES-D 10 scores, 5.37 ± 0.58, when compared with those in the middle, 2.13 ± 0.52, and lowest tertiles, 2.47 ± 0.58. No associations between the 4 other candidate sites and depressive symptoms were observed.

Increased mtDNA heteroplasmy at m.13514A>G is associated with depressive symptoms in older men. Heteroplasmy may represent a novel biological risk factor for depression

Full Text: https://doi.org/10.1002/gps.4928

 

July 03, 2018

SAN FRANCISCO, June 20, 2018—Accurately measuring loss of skeletal muscle mass can help improve care for older men, who may be at risk of falls, mobility problems and other poor health outcomes due to age-related loss of strength. However, results from dual x-ray absorptiometry (DXA) testing — which is typically used to measure muscle mass) — often do not correlate well with physical performance, self-reported mobility, falls and other functional outcomes of skeletal muscle loss due to aging. The ability to carefully characterize muscle mass is central our understanding of sarcopenia – the age-related loss of muscle and its accompanying decline in physical performance.

 

In a prospective study of more than 1,000 older men, California Pacific Medical Center Research Institute (CPMCRI) scientists and collaborators throughout the U.S. found that a newer non-invasive urine test delivered muscle mass measures that were a more accurate predictor of the development of physical symptoms of sarcopenia than DXA. Furthermore, since the laboratory test is comparable in cost and is easier to administer than DXA, its use could improve access to early detection of loss of muscle in men.

 

In the study, 1,382 men with a mean age of 84.2 years agreed to have their skeletal muscle mass measured with the D3-creatine dilution method laboratory test. The non-invasive test involves swallowing a capsule of D3-creatine, a non-radioactive tracer isotope, and then measuring how much of the isotope is passed through to the urine. Through an algorithm, the amount of muscle mass is then calculated. The men also had a DXA lean mass test, completed a short series of physical performance tests and answered questions about their mobility limitations. The men, who were all part of the large cohort Osteoporotic Fractures in Men (MrOS) longitudinal research project, where then tracked over subsequent years for incidence of recurrent falls and new mobility problems.

 

The CPMCRI team found that even controlling for other factors that might impact health outcomes, such as their activity level and other health conditions, the D3-creatine method was a more accurate predictor of functional outcomes for the men than the DXA lean mass test.

 

“Demonstrating that this  non-invasive and relatively low cost test re is consistently related to  late-life functional outcomes opens up the possibility of improving care for older people, by identifying those at most risk of physical decline” Peggy Cawthon, Senior Scientist, CPMCRI. ”We hope that this test ultimately may be used to help identify novel treatment strategies for this population.”

 

The study is entitled “Strong Relation Between Muscle Mass Determined by D3-Creatine Dilution, Physical Performance and Incidence of Falls And Mobility Limitations in a Prospective Cohort of Older Men.” It appears in the June 12, 2018, issue of the peer-reviewed The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences. Read the abstract here.

About the Osteoporotic Fractures in Men (MrOS) Study

 

The MrOS study is a multi-center study of healthy aging in men that has been ongoing since 2000. It is funded by the National Institutes of Health and facilitated by the San Francisco Coordinating Center, a non-profit, academic research organization that is a collaborative enterprise among researchers from California Pacific Medical Center Research Institute and the UCSF School of Medicine, Department of Epidemiology and Biostatistics.

 

 

About California Pacific Medical Center (CPMC)—A Sutter Health Affiliate

 

At San Francisco’s California Pacific Medical Center, we believe in the power of medicine. We research the most up-to-date treatments, hire the most qualified individuals, and practice the most modern, innovative medicine available. We deliver the highest-quality expert care with kindness and compassion in acute, post-acute and outpatient services, as well as preventive and complementary medicine. As one of California’s largest private, community-based, not-for-profit, teaching medical centers, and a Sutter Health affiliate, we are able to reach deep into our community to provide education, screening and financial support in some of the city’s most underserved neighborhoods. Like us on Facebook, watch us on YouTube and follow us on Twitter. For more information visit our web site at cpmc.org.

May 08, 2018

ABSTRACT
Few pooled analyses of antiresorptive (AR) treatment trials relate short-term changes in bone turnover markers (BTMs) to subsequent fracture reduction. Such information would be useful to assess new ARs or novel dosing regimens. In the Foundation for the National Institutes of Health (FNIH) Bone Quality project, we analyzed individual-level data from 28,000 participants enrolled in 11 bisphosphonate (BP) and three selective estrogen receptor modulator (SERM) placebo-controlled fracture endpoint trials. Using BTM results for two bone formation markers (bone-specific alkaline phosphatase [bone ALP] and pro-collagen I N-propeptide [PINP]) and two bone resorption markers (N-terminal and C-terminal telopeptide of type I collagen) and incident fracture outcome data, we performed a meta-regression relating the mean net effect of treatment on change in bone turnover (active minus placebo % difference after 3 to 12 months) to the log of study-wide fracture risk reduction, and used linear regression to plot the best fitting line. Separate analyses were performed for incident morphometric vertebral, nonvertebral, and hip fractures over 1 to 4 years of followup. Change in bone ALP and PINP were available for over 16,000 and 10,000 participants, respectively. For vertebral fracture, the results showed a strong relationship between treatment-related bone ALP or PINP changes and vertebral fracture risk reduction (r2¼0.82 [p<0.001] and r2¼0.75 [p¼0.011], respectively) Relationships were weaker and no longer statistically significant for nonvertebral (r2¼0.33 [p¼0.053] and r2¼0.53 [p¼0.065], respectively) and hip fracture (r2¼0.17 [p¼0.24] and r2¼0.43 [p¼0.11], respectively) outcomes. Analyses limited to BP trials gave similar results. For all fracture types, relationships were weaker and nonsignificant for bone resorption markers. We conclude that short-term AR treatment-related changes in bone ALP and PINP strongly predict vertebral fracture treatment efficacy, but not nonvertebral or hip fracture treatment efficacy. Change in bone formation markers might be useful to predict the anti-vertebral fracture efficacy of new AR compounds or novel dosing regiments with approved AR drugs


Accepted manuscript online December 6, 2017.
Address correspondence to: Douglas Bauer, MD, Department of Medicine, UCSF School of Medicine, 1545 Divisadero Street, San Francisco, CA 94115, USA.
E-mail: DBauer@psg.ucsf.edu


Journal of Bone and Mineral Research, Vol. xx, No. xx, Month 2017, pp 1–9 DOI: 10.1002/jbmr.3355

 

May 02, 2018

Robert A. Hiatt, MD, PhD, professor in the Department of Epidemiology and Biostatistics, is first author on the paper describing the project's early progress and collaborations.  The paper also presents a framework for systematically planning and developing a similar structure for community-based health projects.

The San Francisco Cancer Inititiative is targeting the five most common cancers which account for half of all new cancers in San Francisco: breast, lung and other tobacco-related cancers, prostate, colorectal and liver cancer.

Read the full story at uscf.edu or read the paper in Health Affairs.   Read more about the San Francisco Cancer Initiative (SF CAN).

 

April 30, 2018

The Eureka Research Platform is designed to help investigators conduct direct-to-participant longitudinal research, including cohort studies and randomized controlled trials.  The platform uses technology developed for the Health eHeart Study, and enables eConsent, online surveys, collection of data from wearable sensors, devices and smartphones, and flexible messaging for reminders and behavioral interventions.  Integration with medical records is coming soon.  Learn more about the platform here.

 

March 02, 2018

The Osteoporotic Fractures in Men (MrOS) Study, a study of healthy aging with a focus on osteoporosis and fractures in 5,994 older men 65 years and older, has released over 16 years of prospective data on MrOS Online https://mrosdata.sfcc-cpmc.net/.

 

MrOS Online provides data, documentation, and study procedures from the multi-center MrOS Study.  With over 41,000 variables across seven time points, the MrOS Online database includes:

 

  • Assessment of falls, fractures, and mortality
  • Performance tests and lifestyle questionnaires
  • Objective and subjective measures of physical activity
  • Data from x-ray images, DXA, QCT, and HRpQCT scans
  • Objective and subjective sleep data from the MrOS Sleep ancillary study (n=3,135)
  • Tracking of cardiovascular events from the MrOS Sleep ancillary study
  • Oral health assessments from the MrOS Dental ancillary visit (n=1,353)
  • Biospecimen data, including serum chemistry, hormones, and cytokines

 

The online database is available to the public and anyone who registers and accepts the terms of an online data use agreement can download or explore study data. Please note that only a subset of datasets from the MrOS archives are currently available online. Additional datasets will be publicly released in the near future.

 

The NIA blog/announcement can be found here:

https://www.nia.nih.gov/research/blog/2017/11/release-mros-dataset-offers-new-opportunities-investigators

 

October 03, 2017

Clinical trials of new drugs for the prevention of fracture are extremely expensive and typically go on for at least 3 years. Investigators have tried for decades to find a new more efficient way of conducting these trials more efficiently. The Foundation for NIH project on Bone Quality at the SFCC has discovered that hip BMD is a good surrogate for hip fracture in clinical trials.

The project has compiled data from over 100,000 participants in over 40 clinical trials. They have pooled all of this data together to create the most powerful existing tool for studying ways to make clinical trials more efficient. The project compared changes in hip BMD during the course of these trials and the change in risk of hip fracture. The scientists discovered that every 1% improvement in hip BMD in the trials accurately predicted about a 5% decrease in the risk of hip fractures. This result was presented at a recent conference held by the FDA about new guidelines for clinical trials and has been submitted to FDA to consider revising their guidelines to accept BMD as a “surrogate” to allow clinical trials to use hip BMD as an endpoint for trials to approve drug therapies for prevention of fracture. This would be a revolutionary change in approval of new treatments for osteoporosis.

 

October 03, 2017

High levels of mitochondrial DNA (mtDNA) heteroplasmy, a mixture of normal and mutated mtDNA molecules in a cell, lead to inherited mitochondrial diseases with neurological, sensory, and movement impairments. We measured mtDNA heteroplasmy at twenty disease-causing sites for associations with neurosensory and mobility function among elderly participants from a community-based study of aging.

 

May 01, 2016

In a study from MrOS from the SF Coordinating Center and led by Dr. Doug Bauer, we found that high levels of thyroid hormone that were not known to the patient or physician, indicated a 2.5 to 3.6 times greater chance of becoming frail later in life. This is a treatable condition that might lead to wasting bone and muscle.


(See abstract Virginii VS, et al. Subclinical thyroid dysfunction and frailty among older men. J Clin Endocrinol Metab 2015;100:4524-32.)