Australian researchers have made a discovery about telomeres that may have implications for aging, heart disease, cancer, and other age-related diseases.

So, what are telomeres?

Each of the chromosomes that store our genetic information has a telomere at each end. This protective cap consists of a specific DNA sequence that is repeated thousands of times and has two purposes: firstly, it protects the coding regions of the chromosomes and prevents them from being damaged, and secondly, it acts as a clock that controls the number of replications a cell can undergo; this is thought to act as a quality control system to ensure that aged and potentially damaged cells do not remain in circulation.

BIRMINGHAM, Ala. — 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.

Mitochondrial dysfunction is associated with many mitochondrial diseases, most of which are the result of dysfunctional mitochondrial oxidative phosphorylation (OXPHOS). Mitochondrial OXPHOS accounts for the generation of most of the cellular adenosine triphosphate (ATP) in a cell. The OXPHOS function largely depends on the coordinated expression of the proteins encoded by both nuclear and mitochondrial genomes. The human mitochondrial genome encodes for 13 polypeptides of the OXPHOS, and the nuclear genome encodes the remaining more than 85 polypeptides required for the assembly of OXPHOS system. Mitochondrial DNA (mtDNA) depletion impairs OXPHOS that leads to mtDNA depletion syndromes (MDSs)^{1, 2}. The MDSs are a heterogeneous group of disorders, characterized by low mtDNA levels in specific tissues. In different target organs, mtDNA depletion leads to specific pathological changes. MDS results from the genetic defects in the nuclear-encoded genes that participate in mtDNA replication, and mitochondrial nucleotide metabolism and nucleotide salvage pathway^{1, 4,5,6,7,8,9,10}. mtDNA depletion is also implicated in other human diseases such as mitochondrial diseases, cardiovascular^{11, 12}, diabetes^13,14,15, age-associated neurological disorders^16,17,18, and cancer^{19,20,21,22,23,24,25}.

A general decline in mitochondrial function has been extensively reported during aging^{26,27,28,29,30,31,32,33}. Furthermore, mitochondrial dysfunction is known to be a driving force underlying age-related human diseases^{16,17,18, 34,35,36}. A mouse that carries elevated mtDNA mutation is also shown to present signs of premature aging^{37, 38}. In addition to mutations in mtDNA, studies also suggest a decrease in mtDNA content and mitochondrial number with age^{27, 29, 32, 33, 39}. Notably, there is an age-related mtDNA depletion in a number of tissues^40,41,42. mtDNA depletion is also frequently observed among women with premature ovarian aging⁴³. Low mtDNA copy number is linked to frailty and, for a multiethnic population, is a predictor of all-cause mortality⁴⁴. A recent study revealed that humans on an average lose about four copies of mtDNA every ten years. This study also identified an association of decrease in mtDNA copy number with age-related physiological parameters³⁹.

To help define the role of mtDNA depletion in aging and various diseases, we created an inducible mouse expressing, in the polymerase domain of POLG1, a dominant-negative (DN) mutation that induces depletion of mtDNA in the whole animal. Interestingly, skin wrinkles and visual hair loss were among the earliest and most predominant phenotypic changes observed in these mice. In the present study, we demonstrate that mtDNA depletion-induced phenotypic changes can be reversed by restoration of mitochondrial function upon repletion of mtDNA.