Hair Loss Study: Scientists reverse aging-associated skin wrinkles and hair loss in a mouse model

A gene mutation causes wrinkled skin and hair loss; turning off that mutation restores the mouse to normal appearance.

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."

Story Source:

Materials provided by University of Alabama at Birmingham. Note: Content may be edited for style and length.

Journal Reference:

1. Bhupendra Singh, Trenton R. Schoeb, Prachi Bajpai, Andrzej Slominski, Keshav K. Singh. Reversing wrinkled skin and hair loss in mice by restoring mitochondrial function. Cell Death & Disease, 2018; 9 (7) DOI: 

PAGE CITATION:

University of Alabama at Birmingham. "Scientists reverse aging-associated skin wrinkles and hair loss in a mouse model: A gene mutation causes wrinkled skin and hair loss; turning off that mutation restores the mouse to normal appearance.." ScienceDaily. ScienceDaily, 20 July 2018. <www.sciencedaily.com/releases/2018/07/180720112808.htm>.

Hair Loss Study: Experimental drug reverses hair loss and skin damage linked to fatty diet, shows a new study in mice

The research advances the search for compounds that may someday accelerate wound healing and reverse balding in a series of experiments with mice, Johns Hopkins investigators have used an experimental compound to successfully reverse hair loss, hair whitening and skin inflammation linked by previous studies to human diets heavy in fat and cholesterol.

The investigators say the compound halts the production of certain fats called glycosphingolipids, or GSLs, that are major components of skin and other cell membranes. Current research shows that mice fed a diet high in fat and cholesterol are more likely to have hair discoloration from black to gray to white, extensive hair loss and inflammation of skin exhibited by multiple wounds. Feeding these animals the compound, however, appears to reverse such symptoms.

The Hopkins investigators caution that such results in mice do not mean that the same effects would occur in people, and there is no evidence at this time that the compounds they used would be safe in people. But the findings, they say, do shed light on possible pathways for addressing hair loss and skin wounds in humans with oral or topical medications.

A report on the findings was published July 30 in Scientific Reports.

"Further research is needed, but our findings show promise for someday using the drug we developed for skin diseases such as psoriasis, and wounds resulting from diabetes or plastic surgery," says Subroto Chatterjee, Ph.D., M.S., M.Sc., professor of pediatrics and medicine at the Johns Hopkins University School of Medicine. Chatterjee conducts research as part of Johns Hopkins Children's Center.

More specifically, previous studies showed that GSLs are prevalent in the cells that make up the uppermost layer of the skin, as well as in cells called keratinocytes that help regulate pigmentation of the eyes, skin and hair.

To determine how disrupting GSLs might affect skin appearance and color, and whether treatment with D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP) -- a human-made compound that halts GSL production -- would reverse any negative effects, Chatterjee and his colleagues first genetically modified a group of mice to have atherosclerosis, a disease in which arteries are clogged by fat deposits.

The researchers then fed one group of these mice a Western diet high in fat and cholesterol, and a second group standard chow. All mice were fed their assigned diets from 12 weeks of age to 20 weeks.

Compared to those fed standard chow, the mice that ate a Western diet lost hair, formed skin lesions and suffered from hair whitening. These results became more severe when the mice continued eating a Western diet for 36 weeks, with 75 percent of the mice having skin, hair loss and multiple skin lesions.

From 20 to 36 weeks of age, mice in both groups were given varying amounts of D-PDMP, either in a capsule or as a liquid, while they ate the same diet. Mice that received 1 milligram and 10 milligrams of D-PDMP in a capsule per kilogram of body weight from 20 to 36 weeks while eating a Western diet started regaining hair and hair color, and their skin inflammation lessened. Treatment with 1 milligram of D-PDMP in a capsule per kilogram of body weight was as effective as 10 milligrams per kilogram as a liquid. This suggests that an encapsulated form of D-PDMP is a better method of drug delivery.

The research team then looked at the skin of the mice's under a microscope and found that mice eating the Western diet experienced an infiltration of neutrophils, a type of white blood cell implicated in inflammation, in various skin areas. Treatment with D-PDMP in a capsule significantly reduced the number of neutrophils, implying reduced skin inflammation and wounding.

Next, the researchers used mass spectrometry analysis, a method of identifying and quantifying the chemical composition of a mixture, to determine ceramide, glucosylceramide and lactosylceramide levels in the mice. Ceramides are a type of lipid, or fat, that helps protect the skin's moisture, and glucosylceramide is the first derivative of ceramide, whereas lactosylceramide, a later derivative of ceramide, activates inflammation.

Compared to mice fed normal chow, those fed a Western diet had decreased total ceramide levels, decreased glucosylceramide and nearly three times more lactosylceramide. Treatment with 1 milligram of D-PDMP in a capsule per kilogram of body weight or 10 milligrams of D-PDMP as a liquid per kilogram of body weight, however, noticeably increased ceramide levels to normal.

"Our findings show that a Western diet causes hair loss, hair whitening and skin inflammation in mice, and we believe a similar process occurs in men who lose hair and experience hair whitening when they eat a diet high in fat and cholesterol," says Chatterjee.

More animal research needs to be done to confirm and expand on the findings, and to determine how well and what amount of D-PDMP might heal wounds and activate hair growth.

"Hopefully someday in the future this can mean faster, more effective recovery from baldness, hair whitening in aging populations and wound healing," says Chatterjee.

Other authors on this paper include Djahida Bedja, Wenwen Yan, Dominica Iocca, Veera Ratnam Bandaru and Nickesh Ramakrishnan of the Johns Hopkins University School of Medicine, and Wenwen Yan of Tongji University.

This study was funded by the National Institutes of Health (PO1HL10715301).

Story Source:

Materials provided by Johns Hopkins Medicine. Note: Content may be edited for style and length.

Journal Reference:

1. Djahida Bedja, Wenwen Yan, Viren Lad, Domenica Iocco, Nickash Sivakumar, Veera Venkata Ratnam Bandaru, Subroto Chatterjee. Inhibition of glycosphingolipid synthesis reverses skin inflammation and hair loss in ApoE−/− mice fed western diet. Scientific Reports, 2018; 8 (1) DOI: 

PAGE CITATION: Johns Hopkins Medicine. "Experimental drug reverses hair loss and skin damage linked to fatty diet, shows new study in mice: The research advances search for compounds that may someday accelerate wound healing and reverse balding." ScienceDaily. ScienceDaily, 30 July 2018. <www.sciencedaily.com/releases/2018/07/180730090152.htm>.

A new drug could ease the distress of men and women who suffer from baldness, according to researchers from The University of Manchester's Centre for Dermatology Research. 

African-American women are prone to hair loss, and new data presented at the American Academy of Dermatology's 74th Annual Meeting in Washington illustrates the scope of this problem, which often goes undiagnosed. Certain styling practices may increase the risk of hair loss in this population; women who are concerned about losing their hair should consider different styling practices and see a dermatologist if they notice any signs of hair loss.