Wrinkles and hair loss are reversed thanks to mitochondrial restoration

Skin wrinkles and hair loss are two of the most commonly reported signs of aging, but a team from the University of Alabama at Birmingham (UAB) demonstrated how these two characteristics from the past can be reversed, at least in a mouse model. Studies conducted on experimental mice by UAB genetics professor Keshav Singh, Ph.D., and colleagues, have shown how a gene mutation leading to mitochondrial dysfunction – known to be linked to aging and disease-related diseases. Age in humans – develop skin wrinkles and significant hair loss within a few weeks. When the gene mutation was disabled and normal mitochondrial function was restored, the same animals lost their wrinkles and recovered thick, normal layers.

"To our knowledge, this observation is unprecedented," says Dr. Singh. "This mouse model should provide an unprecedented opportunity for the development of preventive and therapeutic therapeutic strategies to increase mitochondrial functions for the treatment of cutaneous and capillary pathology associated with aging and other human diseases in which mitochondrial dysfunction play an important role." 19659002] Report of Discoveries in Cell Death & Disease Dr. Singh's team advocates further studies to see if inversion of mitochondrial dysfunction related to age could have similar rejuvenating effects on other organs. "Further experiments are needed to determine whether phenotypic changes in other organs can also be reversed at the wild level by mtDNA restoration [mitochondrial DNA]," the researchers write in their article, entitled "Invert wrinkled skin and hair loss". mouse by restoring mitochondrial function. "

The mtDNA depletion and mitochondrial dysfunction are associated with many mitochondrial diseases, most of which are caused by mitochondrial oxidative phosphorylation (OXPHOS), the process that generates adenosine triphosphate (ATP ) their energetic currency

A gradual decline in mitochondrial function has also been linked to aging and is known to cause age-related diseases.Studies have shown for example how the increase in mutations of mitochondrial DNA leads to signs of premature aging in mice

The OXPHOS function in mitochondria depends on the expression of mitochondrial proteins encoded by genes carried by mitochondrial and nuclear DNA To study more closely how the depletion of mitochondrial DNA and mitochondrial dysfunction could play a role in the aging The team developed the mtDNA-depleter mouse model, in which a key nuclear mtDNA gene is mutated by adding the doxycycline (dox) antibiotic to food or drinking water. Gene mutation effectively leads to the depletion of mitochondrial DNA, including reduction of mtDNA, reduction of mitochondrial gene expression and reduction of OXPHOS activity.

mtDNA-depleter mice develop normally up to the age of 8 weeks. that the researchers started to administer doxycycline. In the four weeks following the induction of doxycycline and the depletion of mitochondrial DNA, animals began to develop sparse gray hair, hair loss (alopecia) and abnormal sebaceous glands. Other studies have suggested that hair loss was not caused by a reduced number of hair follicles, but by dysfunctional follicles that could not produce normal hair. MtDNA-depleter mice developed rough, thickened skin – wrinkles were more pronounced in female mice than in male mice – in addition to sluggish movements and lethargy that recalled the phenotypic changes that would occur naturally with aging. "… these studies indicate that the depletion of mtDNA in animals induces mainly skin wrinkles due to epidermal hyperplasia and hyperkeratosis, and alopecia due to abnormal development of hair follicles and to the loss of ability to produce hair ".

Skin wrinkles are not just a feature of the natural or "intrinsic" process of aging. Prolonged exposure to the sun, long-term smoking and other environmental aggressions can also lead to "extrinsic" skin aging. "Mitochondrial dysfunction is involved in intrinsic and extrinsic aging," the authors note.

mtDNA-depleter mice appeared to demonstrate intrinsic and extrinsic aging characteristics. While their skin cells expressed markers of intrinsic aging, coarse skin wrinkles and the presence of inflammatory cells and the expression of inflammatory genes in the dermis of mitochondrial DNA depleting mice treated with doxycycline were features extrinsic aging of the skin in humans

. Interestingly, when the doxycycline treatment was removed from the mtDNA-depleting mice and their mitochondrial DNA was restored, the wrinkled and hairless animals gradually underwent visual rejuvenation. After one month of stopping antibiotic treatment, their skin wrinkles had disappeared, their skin structure, including hair follicles and sebaceous glands, had normalized and was almost free of inflammatory cells, and their hair was growing back. "Epidermal hyperplasia, abnormal sebaceous glands, and defects in hair follicle development and hair shaft formation were absent in mtDNA-replet mice," note the researchers. "… after 1 month of weaning, skin wrinkles and hair loss came back, and the animals appeared relatively normal compared to wild animals of the same age."

The authors say that mitochondria are regulators of aging skin and hair loss is unexpected. "This observation is surprising and suggests that the epigenetic mechanisms underlying the crosstalk between mitochondria and nuclei must play an important role in restoring the normal phenotype of skin and hair," they write. "Together, this mouse model should provide an unprecedented opportunity for the development of preventive and therapeutic development strategies to increase mitochondrial functions for the treatment of cutaneous and capillary pathology associated with aging and other human diseases in which Mitochondrial dysfunction plays an important role. "