Breaking and Then Fixing Mouse Biochemistry is Not Reversing Aging
A recent example of research in which researchers break the mitochondrial biochemistry of mice and then reverse that breakage is doing the rounds in the press, being pitched as a reversal of aging. It is not a reversal of aging, however, and I'd say that the researchers involved still have to prove that the particular breakage that they engineered is in fact relevant in normal aging. The appearance of similar outcomes between the breakage and aging does not mean that it is relevant.
Why is this the case? Aging is an accumulation of specific forms of biochemical damage that leads to widespread tissue dysfunction. Given that, the outcome of any form of damage that leads to widespread tissue dysfunction inevitably shares some appearances with normal aging. Since that outcome results from entirely different root causes, however, it is of little relevance or use to developing a better understanding of aging. Mammalian biochemistry can be severely broken and damaged in a near infinite number of ways that do not occur in aging to any significant degree, which is why one has to read the details carefully when this sort of work is published. The media never gets it right.
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.
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.
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. 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.