Wrinkles and Hair Loss Reversed through Mitochondrial Restoration
Skin wrinkles and hair loss are two of the most commonly bemoaned signs of aging, but a team at the University of Alabama at Birmingham (UAB) has now demonstrated how both of these telltale features of passing years can be reversed, at least in a mouse model. Studies in experimental mice by UAB professor of genetics Keshav Singh, Ph.D., and colleagues, showed how a gene mutation that leads to mitochondrial dysfunction – which is known to be linked with aging and age-related diseases in humans – caused the animals to develop skin wrinkles and extensive hair loss within weeks. When the gene mutation was switched off and normal mitochondrial function was restored the same animals lost their wrinkles and regrew thick, normal coats.
“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 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.”
Reporting on the findings in Cell Death & Disease, Dr. Singh’s team advocates further studies to see if reversing age-related mitochondrial dysfunction could have similar rejuvenating effects on other organs. “Further experiments are required to determine whether phenotypic changes in other organs can also be reversed to wild-type level by restoration of mtDNA [mitochondrial DNA],” the researchers write in their paper, which is titled, “Reversing wrinkled skin and hair loss in mice by restoring mitochondrial function.”
MtDNA depletion and mitochondrial dysfunction is associated with many mitochondrial diseases, most of which are caused by dysfunctional mitochondrial oxidative phosphorylation (OXPHOS), the process that generates the adenosine triphosphate (ATP) that cells use as their energy currency.
A gradual decline in mitochondrial function has also been linked with aging, and is known to drive age-related diseases. Studies have, for example, shown how increased mtDNA mutations lead to signs of premature aging in mice.
OXPHOS function in mitochondria depends on the expression of mitochondrial proteins that are encoded by genes carried both by mitochondrial DNA and by nuclear DNA. To investigate more closely how mtDNA depletion and mitochondrial dysfunction might play a role in aging the team developed the mtDNA-depleter mouse model, in which a key nuclear mtDNA gene is mutated by adding the antibiotic doxycycline (dox) to food or drinking water. The gene mutation effectively leads to mtDNA depletion, including reduced mtDNA content, reduced mitochondrial gene expression, and reduced OXPHOS activity.
The mtDNA-depleter mice appeared to develop normally until they were 8 weeks of age, and it was at this point that the researchers started to administer doxycycline. Within four weeks of doxycycline induction and mtDNA depletion, the animals started to develop grey, thinning hair and hair loss (alopecia), and abnormal sebaceous glands. Further studies suggested that hair loss wasn’t caused by reduced numbers of hair follicles, but by dysfunctional follicles that couldn’t produce normal hair. The mtDNA-depleter mice all developed thickened, wrinkled skin – the wrinkles were more prominent in female mice than in male mice – in addition to slowed movements and lethargy that were reminiscent of phenotypic changes that would be expected to occur naturally with aging. “ … these studies indicate that mtDNA depletion in the whole animal predominantly induces skin wrinkles due to epidermal hyperplasia and hyperkeratosis, and alopecia because of abnormal hair follicle development and the loss of ability to produce hair shafts,” the authors write.
Skin wrinkles aren’t just a characteristic of the natural, or “intrinsic” process of aging. Prolonged exposure to sun, long-term smoking, and other environmental insults can also lead to “extrinsic” skin aging. “Mitochondrial dysfunction is implicated in both intrinsic and extrinsic aging,” the authors point out.
The mtDNA-depleter mice seemed to demonstrate features of both intrinsic and extrinsic aging. While their skin cells expressed markers of intrinsic aging, the coarse skin wrinkles, and presence of inflammatory cells and inflammatory gene expression in the dermis of the doxycycline-treated mtDNA-depleter mice were characteristics of extrinsic aging of the skin in humans.
Interestingly, when doxycycline treatment was withdrawn from mtDNA-depleter mice and their mtDNA was restored, the wrinkled, hairless animals gradually underwent visual rejuvenation. Within a month of stopping antibiotic treatment their skin wrinkles had disappeared, their skin structure, including hair follicles and sebaceous glands, had normalized and was just about free of inflammatory cells, and their hair had grown back. “The epidermal hyperplasia, abnormal sebaceous glands, and defects in hair follicle development and hair shaft formation were absent in the mtDNA-repleter mice,” the researchers note. “… after 1 month of dox withdrawal, the skin wrinkles and hair loss reverted, and the animals appeared relatively normal when compared to the age-matched, wild-type animals.”
The authors say the finding that mitochondria are regulators of skin aging and loss of hair is unexpected. “This observation is surprising and suggests that epigenetic mechanisms underlying mitochondria-to-nucleus crosstalk must play an important role in the restoration of normal skin and hair phenotype,” they write. “Together, this mouse model should provide an unprecedented opportunity for the development of preventative 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.”