Scientists reverse Aging-associated skin wrinkles and hair loss in a mouse model

Wrinkled skin and hair loss are hallmarks of aging. What if they could be reversed?

Keshav Singh, Ph.D., and colleagues have done just that, in a mouse model developed at the University of Alabama at Birmingham. When a mutation leading to mitochondrial dysfunction is induced, the mouse develops wrinkled skin and extensive, visible hair loss in a matter of weeks. When the mitochondrial function is restored by turning off the gene responsible for mitochondrial dysfunction, the mouse returns to smooth skin and thick fur, indistinguishable from a healthy mouse of the same age.

"To our knowledge, this observation is unprecedented," said Singh, a professor of genetics in the UAB School of Medicine.

Importantly, the mutation that does this is in a nuclear gene affecting mitochondrial function, the tiny organelles known as the powerhouses of the cells. Numerous mitochondria in cells produce 90 percent of the chemical energy cells need to survive.

In humans, a decline in mitochondrial function is seen during aging, and mitochondrial dysfunction can drive age-related diseases. A depletion of the DNA in mitochondria is also implicated in human mitochondrial diseases, cardiovascular disease, diabetes, age-associated neurological disorders and cancer.

"This mouse model," Singh said, "should provide an unprecedented opportunity for the development of preventive and therapeutic drug development strategies to augment the mitochondrial functions for the treatment of aging-associated skin and hair pathology and other human diseases in which mitochondrial dysfunction plays a significant role."

The mutation in the mouse model is induced when the antibiotic doxycycline is added to the food or drinking water. This causes depletion of mitochondrial DNA because the enzyme to replicate the DNA becomes inactive.

In four weeks, the mice showed gray hair, reduced hair density, hair loss, slowed movements and lethargy, changes that are reminiscent of natural aging. Wrinkled skin was seen four to eight weeks after induction of the mutation, and females had more severe skin wrinkles than males.

Dramatically, this hair loss and wrinkled skin could be reversed by turning off the mutation. The photos below show the hair loss and wrinkled skin after two months of doxycycline induction, and the same mouse a month later after doxycycline was stopped, allowing restoration of the depleted mitochondrial DNA.

Little change was seen in other organs when the mutation was induced, suggesting an important role for mitochondria in skin compared to other tissues.

The wrinkled skin showed changes similar to those seen in both intrinsic and extrinsic aging -- intrinsic aging is the natural process of aging, and extrinsic aging is the effect of external factors that influence aging, such as skin wrinkles that develop from excess sun or long-term smoking.

Among the details, the skin of induced-mutation mice showed increased numbers of skin cells, abnormal thickening of the outer layer, dysfunctional hair follicles and increased inflammation that appeared to contribute to skin pathology. These are similar to extrinsic aging of the skin in humans. The mice with depleted mitochondrial DNA also showed changed expression of four aging-associated markers in cells, similar to intrinsic aging.

The skin also showed disruption in the balance between matrix metalloproteinase enzymes and their tissue-specific inhibitor -- a balance of these two is necessary to maintain the collagen fibers in the skin that prevent wrinkling.

The mitochondria of induced-mutation mice had reduced mitochondrial DNA content, altered mitochondrial gene expression, and instability of the large complexes in mitochondria that are involved in oxidative phosphorylation.

Reversal of the mutation restored mitochondrial function, as well as the skin and hair pathology. This showed that mitochondria are reversible regulators of skin aging and loss of hair, an observation that Singh calls "surprising."

"It suggests that epigenetic mechanisms underlying mitochondria-to-nucleus cross-talk must play an important role in the restoration of normal skin and hair phenotype," Singh said, who has a secondary UAB appointment as professor of pathology. "Further experiments are required to determine whether phenotypic changes in other organs can also be reversed to wildtype level by restoration of mitrochondrial DNA."

News source: https://www.rdmag.com

Singh B, Schoeb TR, Bajpai P, Slominski A, Singh KK. Reversing wrinkled skin and hair loss in mice by restoring mitochondrial function.
Cell Death Dis. 2018, 9:735, DOI: 10.1038/s41419-018-0765-9

Biochemist, physicist team to see antibacterial triclosan(TCS) deform mitochondria

Julie Gosse, a University of Maine associate professor of molecular and biomedical sciences, has scanned the supermarket aisles for products that contain triclosan(TCS), a synthetic antibacterial agent.

Since the '90s, TCS has been in a slew of consumer products, including facial cleansers, toothpaste, mouthwash and hand sanitizers.

For years, Gosse has studied TCS, which for decades also has been used as a hospital scrub to reduce risk of infection.

She became interested in examining triclosan when listening to a talk by Environmental Protection Agency scientist Susan Richardson and noting that the molecular structure of TCS resembles the molecular structure of dioxins, which are toxic environmental pollutants.

In 2016, the Food and Drug Administration banned triclosan from consumer bar soaps, liquid soaps and body washes. At that time, the FDA challenged manufacturers to either prove TCS was more effective at killing germs than plain soap, or to remove it from their soap product within a year.

The antimicrobial agent, which is readily absorbed into the skin and the lining of the mouth, has recently been found to have detrimental effects on human fertility, development, thyroid function and immunology, and has been associated with increased occurrence of asthma.

Then, about six months ago, the FDA also announced a ban on products such as hand washes and antiseptic rubs containing TCS that are used in medical settings.

There's no such ban on Colgate Total, the popular toothpaste that contains TCS. That's because it's been found to be more effective at treating gingivitis than toothpaste without it.

Gingivitis is an important health concern as it can lead to tooth loss. And research has indicated the bacteria that causes periodontitis can enter a person's bloodstream and harm the heart and lungs.

Gosse understands why people with gingivitis would use Colgate Total; she just wants millions of people without gingivitis who also use the product to be aware of possible risks.

"Our job is to do the best science we can do and make people aware," she says. "As scientists, we communicate our findings, and the public or companies or government decides what they should do."

News source: https://medicalxpress.com/news/2018-05-biochemist-physicist-team-antibacterial-tcs.html

Brain Mitochondria, Aging and Parkinson’s Disease

This paper reconsiders the role of mitochondria in aging and in Parkinson's Disease (PD). The most important risk factor for PD is aging. Alterations in mitochondrial activity are typical of aging. Mitochondrial aging is characterized by decreased oxidative phosphorylation, proteasome activity decrease, altered autophagy, and mitochondrial dysfunction. Beyond declined oxidative phosphorylation, mitochondrial dysfunction consists of a decline of beta-oxidation as well as of the Krebs cycle. Not inherited mitochondrial DNA (mtDNA) mutations are acquired over time and parallel the decrease in oxidative phosphorylation. Many of these mitochondrial alterations are also found in the PD brain specifically in the substantia nigra (SN). mtDNA deletions and development of respiratory chain deficiency in SN neurons of aged individuals as well as of individuals with PD converge towards a shared pathway, which leads to neuronal dysfunction and death. Finally, several nuclear genes that are mutated in hereditary PD are usually implicated in mitochondrial functioning to a various extent and their mutation may cause mitochondrial impairment. In conclusion, a tight link exists between mitochondria, aging, and PD.

News source: www.mdpi.com
Authors: Mario Rango and Nereo Bresolin

Imaging Method Evaluates Cell Functional Changes and Wound Healing

Optical redox ratio maps of fibroblasts isolated from young and aged rats. Red regions correspond to high redox ratios, while blue regions correspond to low ratios. Images courtesy of Olivia Kolenc and Kyle Quinn.

Kyle Quinn, assistant professor of biomedical engineering at the University of Arkansas, has published a review highlighting recent advances in autofluorescence imaging and discussing its role in evaluating cell metabolism.

Autofluorescence is the emission of light by molecules naturally present in cells and tissue when those molecules have absorbed light.

Quinn and graduate student Olivia Kolenc have published an article in Antioxidants & Redox Signaling, explaining that human cells and tissues contain naturally fluorescent molecules that can be imaged and used to assess cell metabolism for a broad spectrum of biomedical applications, including tissue engineering and regenerative medicine.

Autofluorescence imaging of these naturally fluorescent molecules – nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) – can allow researchers to assess the structural organization of mitochondria and biochemical details related to cell metabolism. This can be done through a measurement called an optical redox ratio, which quantifies the relative concentrations of NADH and FAD. The three-dimensional distribution of NADH and FAD within cells can be quantified non-invasively in living tissue by using a multiphoton microscope.

Mitochondria are the organelles – or specialized structures – within cells that are responsible for respiration and energy production.

Traditionally, this imaging technique has been used to monitor cell metabolism during hypoxia and cancer development, Quinn said. But he and Kolenc expect that continued improvement in instrumentation and analysis with these methods will lead to wider applications and further advances in basic science, preclinical research and clinical management of disease. For example, part of Quinn’s research focuses on applying this imaging technique to the study of wound healing.

Quinn is also a co-author of a new study by researchers at Tufts University, where he was a postdoctoral fellow after receiving his doctorate at the University of Pennsylvania. The study highlights some of these new applications and methods for autofluorescence imaging of NADH and FAD.

“Autofluorescence intensity can be a useful metric to noninvasively assess metabolic and functional cellular changes for a variety of biochemical applications,” Quinn said. “We here at the U of A are particularly excited about its use in evaluating wound healing.”

Quinn’s research is supported by the National Institutes of Health, Department of Defense, and the Arkansas Biosciences Insititute. In September of 2017, he received a $1.7 million grant from the NIH to continue developing autofluorescence imaging methods to quantify and understand age-related delays in skin wound healing.

Also in 2017, Quinn published research demonstrating that during the weeks following a heart attack, the injured heart wall acquires more collagen fibers that are significantly less stiff due to a lack of naturally fluorescent fiber crosslinks. That study appeared in Nature Publishing Group’s Scientific Reports.

News source: https://researchfrontiers.uark.edu