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In what appears to be a world first, scientists at the University of Alabama at Birmingham have reversed two of the most common visual signs of aging—skin wrinkles and hair loss—in mice by turning off a gene responsible for mitochondrial dysfunction [1].

Study abstract

Mitochondrial DNA (mtDNA) depletion is involved in mtDNA depletion syndromes, mitochondrial diseases, aging and aging-associated chronic diseases, and other human pathologies. To evaluate the consequences of depletion of mtDNA in the whole animal, we created an inducible mtDNA-depleter mouse expressing, in the polymerase domain of POLG1, a dominant-negative mutation to induce depletion of mtDNA in various tissues. These mice showed reduced mtDNA content, reduced mitochondrial gene expression, and instability of supercomplexes involved in oxidative phosphorylation (OXPHOS) resulting in reduced OXPHOS enzymatic activities. We demonstrate that ubiquitous depletion of mtDNA in mice leads to predominant and profound effects on the skin resulting in wrinkles and visual hair loss with an increased number of dysfunctional hair follicles and inflammatory responses. Development of skin wrinkle was associated with the significant epidermal hyperplasia, hyperkeratosis, increased expression of matrix metalloproteinases, and decreased expression of matrix metalloproteinase inhibitor TIMP1. We also discovered markedly increased skin inflammation that appears to be a contributing factor in skin pathology. Histopathologic analyses revealed dysfunctional hair follicles. mtDNA-depleter mice also show changes in expression of aging-associated markers including IGF1R, KLOTHO, VEGF, and MRPS5. mtDNA-repleter mice showed that, by turning off the mutant POLG1 transgene expression, mitochondrial function, as well as the skin and hair pathology, is reversed to wild-type level. To our knowledge that restoration of mitochondrial functions can reverse the skin and hair pathology is unprecedented.

Mitochondrial dysfunction in brief

Mitochondria are tiny organelles inside your cells. Their job is to produce as much as 90% of adenosine triphosphate, or ATP, which is the molecule responsible for powering cellular machinery. Mitochondria have their own DNA, known as mtDNA, which is not the same as the DNA contained in the cell’s nucleus. mtDNA is known to degrade with aging, and this degradation has been implied in multiple aging-related pathologies, including diabetes, cancer, cardiovascular diseases, and mitochondrial diseases. Mitochondrial dysfunction is one of the hallmarks of aging [2]; thus, it is also a target of candidate rejuvenation biotechnologies, such as allotopic expression, as the SENS Research Foundation has proposed.

The study

The main goal of this study wasn’t explicitly that of undoing visual signs of aging; rather, the scientists wanted to observe the effects that the depletion of mitochondrial DNA would have on mice as a whole. To this end, they engineered mice carrying a mutation that could induce depletion of mtDNA in several of the animals’ tissues; the mutated gene could be switched on by administering the antibiotic doxycycline to the animals through their feed. Once this was done, the enzyme that allows for mtDNA replication was no longer active, leading to depletion of mitochondrial DNA in the tissues involved.

The mutation impaired the process of oxidative phosphorylation, by which mitochondria produce ATP, and reduced mitochondrial gene expression. After four weeks, mice whose mtDNA replication had been turned off displayed typical signs of skin aging, such as wrinkles, hair loss, reduced hair density, and graying as well as an increase of skin inflammation and changes in aging-related markers, such as IGF1R and KLOTHO. Interestingly, all of these changes are reminiscent of both primary, intrinsic aging, which happens due to internal factors, and secondary, extrinsic aging, which happens due to external factors, such as excessive sun exposure or smoking. The observed changes in aging-related markers bore similarities to primary aging, whereas wrinkles, dysfunction of hair follicles—which led to hair loss—and skin inflammation were similar to secondary aging in humans.

The mice in the experiment also exhibited decreased activity and appeared to be slowed down in their movements—which is perhaps not surprising, as most of their cellular energy was no longer being produced; what was surprising, according to lead author Dr. K. Singh, was that reversing the mutation’s effect also reversed wrinkling and hair loss. Both these effects disappeared within a month from when administration of doxycycline was suspended, to the point that mutated mice could no longer be visually distinguished from control mice of the same age.

This observation suggests that mitochondria play a role as regulators of skin aging and that therapies to enhance mitochondrial function might be employed to treat human aging-related skin pathologies as well as other pathologies driven by mitochondrial dysfunction. However, as the effects of this genetic alteration seemed to be of little consequence for tissues other than skin, more studies will be needed to assess whether this type of therapy might prove useful in the treatment of conditions involving other bodily tissues.

Conclusion

What the researchers here have essentially done is broken the biochemistry of the mouse mitochondria, which led to some aging-like symptoms, and then reversed that breakage. This does not imply that the damage they have done is relevant to normal physiological aging, and the researchers will need to follow up this study in order to determine if it is relevant to normal aging or not.

Literature

[1] Singh, B., Schoeb, T. R., Bajpai, P., Slominski, A., & Singh K. K. (2018). Reversing wrinkled skin and hair loss in mice by restoring mitochondrial function, Cell Death & Diseases, 9.

[2] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.

About the author

Nicola Bagalà

Nicola is a bit of a jack of all trades—a holder of an M.Sc. in mathematics; an amateur programmer; a hobbyist at novel writing, piano and art; and, of course, a passionate life extensionist. After his interest in the science of undoing aging arose in 2011, he gradually shifted from quiet supporter to active advocate in 2015, first launching his advocacy blog Rejuvenaction before eventually joining LEAF. These years in the field sparked an interest in molecular biology, which he actively studies. Other subjects he loves to discuss to no end are cosmology, artificial intelligence, and many others—far too many for a currently normal lifespan, which is one of the reasons he’s into life extension.
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