Breaking News
March 24, 2019 - Researchers track effects of epigenetic marks carried by sperm chromosomes
March 24, 2019 - AHA News: Family Adopts Three Children With Three Different Heart Conditions
March 24, 2019 - Research into opioid painkillers could provide clues for safer drug development
March 23, 2019 - Lung cancer survivor recounts her lifetime struggles
March 23, 2019 - Radial and femoral approach for PCI achieve similar results in terms of survival
March 23, 2019 - Study sheds light on the optimal timing of coronary angiography in NSTEMI patients
March 23, 2019 - Excess hormones could cause a condition that can lead to blindness in women, study finds
March 23, 2019 - Dramatic shifts in first-time opioid prescriptions bring hope, concern
March 23, 2019 - Antidepressant drugs may not work when neurons are out of shape
March 23, 2019 - TTUHSC El Paso to establish endowed chair in neurology through a major grant
March 23, 2019 - New device approved by FDA for treating patients with moderate-to-severe heart failure
March 23, 2019 - People with peripheral artery disease have lower Omega-3 Index, shows research
March 23, 2019 - Trigger warnings have minimal impact on how people respond to content, shows research
March 23, 2019 - Gilead Announces Data From Two Studies Supporting Further Development of GS-6207, a Novel, Investigational HIV-1 Capsid Inhibitor as a Component of Future Long-Acting HIV Therapies
March 23, 2019 - Selfish genetic elements amplify inflammation and age-related diseases
March 23, 2019 - Study provides new understanding of how the brain recovers from damage caused by stroke
March 23, 2019 - CRISPR/Cas libraries could revolutionize drug discovery
March 23, 2019 - Allergic reaction during pregnancy may alter sexual-development in offspring’s brain
March 23, 2019 - Seeing through a robot’s eyes helps those with profound motor impairments
March 23, 2019 - Recent research shows that ease of breastfeeding after C-section differs culturally
March 23, 2019 - Newly discovered parameters offer more control over efficient release of drugs
March 23, 2019 - ‘De-tabooing’ of abortion- Women would like more support from health care community
March 23, 2019 - Anti-TB drugs can increase susceptibility to Mtb reinfection
March 23, 2019 - New survey indicates need of attention to neglected tropical diseases
March 23, 2019 - Innovative in vitro method to develop easy-to-swallow medicine for children and older people
March 23, 2019 - Sugary drinks could raise risk of early deaths finds study
March 23, 2019 - Lian wins ENGINE grant for stem-cell-based therapy to treat Type 1 diabetes
March 23, 2019 - Overall, Physicians Are Happy and Enjoy Their Lives
March 23, 2019 - Researchers discover how blood vessels protect the brain during inflammation
March 23, 2019 - CDC study shows modest improvement in optimal hospital breastfeeding policy
March 23, 2019 - Family-based prevention program to reduce alcohol use among older teens
March 23, 2019 - Remote monitoring of implanted defibrillators in heart failure patients prevents hospitalizations
March 23, 2019 - Appropriate doffing of personal protective equipment may reduce healthcare worker contamination
March 23, 2019 - Window screens can suppress mosquito populations, reduce malaria in Tanzania
March 23, 2019 - Researchers discover new biomarker for postoperative liver dysfunction
March 23, 2019 - Pregnancy history may be linked to cognitive function in older women, finds study
March 23, 2019 - Study shows ticagrelor is equally safe and effective as clopidogrel after heart attack
March 23, 2019 - FDA Approves First Drug for Postpartum Depression, Zulresso (brexanolone)
March 23, 2019 - New guidelines outline new treatment management for psoriasis
March 23, 2019 - Thermally abused cooking oil may promote progression of breast cancer
March 23, 2019 - High-fructose corn syrup fuels growth of colon tumors in mice
March 23, 2019 - Partnership aims at establishing best practices to promote diversity in clinical trials
March 23, 2019 - New study examines presence of microbes in tap water from residences, office buildings
March 23, 2019 - Early life trauma may affect brain structure, contribute to major depressive disorder
March 23, 2019 - NIH starts clinical trial of drug to treat cravings associated with opioid use disorder
March 23, 2019 - Cervix bacteria, immune factors could be a warning signal of premature birth, reports new research
March 23, 2019 - Worst-ever emergency care performance figures underscore the need to focus on staffing
March 23, 2019 - The Current issue of “The view from here” is concerned with Cancer
March 23, 2019 - Mouse model validates how ‘good’ and ‘bad’ bacteria affect acne
March 23, 2019 - Individual amygdala neurons respond to touch, imagery and sounds
March 23, 2019 - Combination of two topical creams can prevent cancer
March 23, 2019 - Study suggests depression screening when assessing African-Americans for schizophrenia
March 23, 2019 - New electronic support system for choosing drug treatment based on patient’s genotype
March 23, 2019 - First-of-its-kind study provides pregnancy statistics of imprisoned U.S. women
March 23, 2019 - Marinus Pharmaceuticals Initiates Phase 3 Study in Children with PCDH19-Related Epilepsy
March 23, 2019 - Laparoscopy: MedlinePlus Lab Test Information
March 23, 2019 - Shellfish allergies: can they be treated?
March 23, 2019 - Toilet seat heart monitoring system
March 23, 2019 - Researchers identify way to improve common treatment for PTSD
March 23, 2019 - High potency cannabis use linked to psychosis finds study
March 23, 2019 - Evoke Pharma Submits Response to FDA Review Letter for Gimoti NDA
March 23, 2019 - Tracking HIV’s ever-evolving genome in effort to prioritize public health resources
March 23, 2019 - Scientists grow most sophisticated brain organoid to date
March 23, 2019 - ADHD drug raising risk of psychosis
March 22, 2019 - FDA approves brexanolone, first drug developed to treat postpartum depression
March 22, 2019 - Gruesome cat and dog experiments by the USDA exposed
March 22, 2019 - Ball pits used in children’s physical therapy may contribute to germ transmission
March 22, 2019 - Long-term use of inexpensive weight-loss drug may be safe and effective
March 22, 2019 - FDA Approves Sunosi (solriamfetol) for Excessive Daytime Sleepiness Associated with Narcolepsy or Obstructive Sleep Apnea
March 22, 2019 - Anti-Müllerian Hormone Test: MedlinePlus Lab Test Information
March 22, 2019 - Finding the right exercise, diet aids for HIV patients
March 22, 2019 - Health Plans For State Employees Use Medicare’s Hammer On Hospital Bills
March 22, 2019 - Researchers develop new tool for imaging large groups of neurons in living animals
March 22, 2019 - Certain bacteria and immune factors in vagina may cause or protect against preterm birth
March 22, 2019 - Research identifies guidelines for prioritizing hepatitis C treatment in U.S. prisons
March 22, 2019 - Novel breath test could pave new way to non-invasively measure gut health
March 22, 2019 - Pharmaceutical and personal care products may result in new contaminants in waterways
March 22, 2019 - New model could revolutionize the way researchers investigate spread of pathogens
March 22, 2019 - MSU professor receives NSF CAREER grant for biosensor diagnostics
March 22, 2019 - High-fat, high-sugar diet in mouse mothers causes problems in the hearts of offspring
Researchers reveal molecular structure of ‘anti-aging’ protein

Researchers reveal molecular structure of ‘anti-aging’ protein

image_pdfDownload PDFimage_print

Researchers from UT Southwestern’s Charles and Jane Pak Center for Mineral Metabolism and Clinical Research and Internal Medicine’s Division of Nephrology recently published work in Nature that reveals the molecular structure of the so-called “anti-aging” protein alpha Klotho (a-Klotho) and how it transmits a hormonal signal that controls a variety of biologic processes. The investigation was performed in collaboration with scientists from New York University School of Medicine and Wenzhou Medical University in China.

Studies at UTSW two decades ago by Dr. Makoto Kuro-o, Professor of Pathology, demonstrated that mice lacking either a-Klotho or the hormone FGF23 suffered from premature and multiple organ failure as well as other conditions, including early onset cardiovascular disease, cancer, and cognitive decline. Because defects in a-Klotho lead to symptoms seen in aging, researchers inferred that a-Klotho suppresses aging, leading to great interest in how the a-Klotho protein might work together with the hormone FGF23 to fulfill their roles.

a-Klotho can exist on the surface of a cell or can be released from the cell and circulate in body fluids, including the blood, as soluble a-Klotho. The cell-attached form and the circulating form of a-Klotho were previously and universally believed to serve completely different functions.

“The a-Klotho gene [then called Klotho] was cloned by Dr. Kuro-o in 1997 shortly before he was recruited here, and during his tenure at UT Southwestern he has carried out the most seminal work in this field,” said Pak Center Director Dr. Orson Moe. “The gene protects against many diseases, including cardiovascular disease, cancer, diabetes, aging, neurodegeneration, and kidney disease. The structure of the a-Klotho protein and how the protein functions, however, largely remained a mystery until this current work.”

By providing a first look at the structure of the protein complex that includes FGF23 and its co-receptors, the FGF receptor and a-Klotho, the most recent study challenges the long-accepted belief that only the cell-attached form of aKlotho can serve as a receptor for FGF23 and hence that FGF23 action is restricted to tissues having the cell-attached form.

Study authors include Dr. Moe, Professor of Internal Medicine and Physiology, and Dr. Ming Chang Hu, Associate Professor of Internal Medicine and Pediatrics. Dr. Moe holds The Charles Pak Distinguished Chair in Mineral Metabolism, and the Donald W. Seldin Professorship in Clinical Investigation. Dr. Hu holds the Makoto Kuro-o Professorship in Bone and Kidney Research.

One of the major, paradigm-changing findings revealed by solving the protein complex structure is that the circulating form of soluble a-Klotho can actually serve as a co-receptor for FGF23. Thus, the soluble form of a-Klotho can go to any cell in the body and act as a co-receptor for FGF23, rendering every cell a possible target of FGF23, representing a major paradigm shift.

“a-Klotho researchers in cancer, aging, neurologic, cardiovascular, and kidney disease will benefit from this research,” Dr. Moe said. “The knowledge of the structure of the protein, along with its molecular binding partners, will enable us to greatly advance the understanding of how a-Klotho works and also how to best design therapeutic strategies and novel agents that can either activate or block FGF23-a-Klotho interaction and signaling as needed.”

Collaboratively led by NYU School of Medicine structural biologist Dr. Moosa Mohammadi, the investigation included researchers from UTSW, the Rockefeller University-based New York Structural Biology Center, and Wenzhou Medical University.

The study provides evidence for how FGF23 signals to cells by forming a complex with a-Klotho and the two other molecular partners. Made by bone cells, the FGF23 hormone travels via the bloodstream to cells in all organs, where it regulates many aspects of mineral metabolism. Abnormal FGF23 levels are found in many disease states. In chronic kidney disease, for example, high FGF23 levels are believed to cause many of the disease’s complications and fatalities.

The researchers say their findings also shed new light on how kidney disease leads to an abnormal thickening of heart muscle tissue called hypertrophy, which is a leading cause of death in people with kidney disease caused by high blood pressure, diabetes, and other illnesses. When damaged kidney tubules can no longer eliminate phosphate in the urine, FGF23 rises, initially as an effort to keep blood phosphate in check. With time, FGF23 can rise to harmful levels.

A prevailing hypothesis has been that very high levels of FGF23 cause hypertrophy in the heart. But the theory remained controversial because heart tissue does not have a-Klotho, which must be present if FGF23 is to signal. The latest findings indicate that a-Klotho can be “delivered” through the bloodstream to organs where it is not normally present. This could potentially launch drug development programs for kidney disease, the researchers said.

“The solution of this protein structure will guide many future studies,” Dr. Moe said. “There are numerous diseases that involve a-Klotho deficiency. Replenishment of a-Klotho by either recombinant protein injection or drugs that increase a patient’s own a-Klotho will have potential therapeutic implications for neurologic, metabolic, cardiovascular and kidney disease, and cancer.”

Source:

http://www.utsouthwestern.edu/newsroom/articles/year-2018/anti-aging-protein.html

Tagged with:

About author

Related Articles