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.
This is not the first study of braking and repairing yields good results. I remember De Grey giving comments in the line that if you drive a car without oil and then add oil or would go better without oil but it doesn't do much about giving insights on how to repair an old car....
Here the biggest concussion is to prove that mitochondria can contribute to aging and that they are one of the key contributors.
This is interesting, though I'd really like to hear your thoughts on the recent successes with mitochondrial transplant.
Reversing an induced break in mouse biochemistry is not reversing aging, but surely this experiment still has some value in modeling aging due to mitochondrial DNA damage?
Are there any updates on the SRF's attempts to allotopically expressing mtDNA genes in the nucleus? It seems like there has not been any news on this for a while now...
Hi there, just a 2 cents,
After reading the full paper, I believe this is a manifestation of aging, intrinsic aging; premature aging in this case. It is very similar to progeroid syndromes, although it seemed more targeting specifics. But, even so, this manifestation is seen in all organs of humans, thus this is premature aging. They describe the mouse has having progeroid head, skin wrinkling, graying fur coat, etc; these are classic manifestations of aging, in acceleration; very reminiscent of HGPS progeria: although not sharing exact same effect, the mice are prematurely aging; or, at least in certain parts - in humans, this manifests in all organs.
Why would this be intrinsic aging ? Mostly because of mtDNA depletion by doxocycline. This, in turn, will cause OXPHOS deficiencies/mitochondrial collapse/cyto C loss/mPTP opening/cell apoptosis/ATP crisis/nuclear blebbing by mitochondrial ROS overproduction/telomere attrition loss (ROS caused/DDR/redox loss/replicative senescence acceleration by checkpoints/epigenetic aging acceleration).. 8-oxodG formation is seen in premature aging, both in mitochondrial and nuclear env, 8-oxodG equal MLSP in mitochondria, they are the causal element to mtDNA deletions in mtDNA itself, mtDNA depletion also. mtDNA depletion is even worse than mtDNA deletion (4977-bp) or mtDNA lesions (8-oxodG). It's like mtDNA is removed altogether/totally absent/mtDNA devoid. mtDNA absence means unsufficient energy/OXPHOS energy crisis. Catastrophic.
It is why mtDNA depletion is seen in premature intrinsic aging in humans. CVD, T2D, ovarian menopause, cancer, brain atrophy, skin wrinkling, etc show mtDNA depletion to some degree. There is 50% cell ATP output loss between 90 and 40 years old during human intrinsic aging in most cells (4000 units down to 2000, five decades later, that means roughly 40 ATP loss/year and, 400 per decade). mtDNA depletion will make ATP depletion ultra-accelerated. mtDNA mutator mice show progeroid premature aging like HGPS. Here, they would be more mtDNA depletion/OXPHOS deficient mice. The severity might be lesser but it seems to boil down to the near same thing.
It's telling when doxocycline induced death 40 days after induction while the rest survived 150 days, it accelerated frailty seen in old age. mtDNA depletion is another manifestation in the constellation of manifestations of intrinsic aging. Here, it happens in acceleration. They may repair/reverse this mtDNA depletion, which would be partial aging reversal, replicative senescence would still be one limit though, likewise for global DNA demethylation of epigenetic clock, progerin accumulation and nuclear chromosome loosening/Histone function loss. As such, it seems not 100% age reversal yet, but more like restoration of 'healthy aging' (back to regular aging speed) rather than premature displayed here.
Just a 2 cents.
CANanonymity,
This is a neat study. It can give some insights on how the mitochondria contribute to aging. However, unless it is combined with an independent repair approach it doesn't do any rejuvenation on its own. The same approach could be used by to simulate accelerated aging even in
isolated tissues. Now if the the was encoded another trigger to activate mitochondria production, recycling out apoptosis , then with the accelerated aging model one can quickly test small molecule compound.
Or the OISIN Platform.
It is not a useless study at all, but not a a breakthrough like p16,53 targets.
Anyway science world like ratchet and ene tiny steps as to the progress, and this approach might be good either for accelerated aging modeling or to investigate various molecular pathways.
Here is something interesting, real cell sized (human egg cell) colloidal robots coming out of MIT, with actual computing circuits incorporated:
"Cell-sized robots can sense their environment"
http://news.mit.edu/2018/cell-sized-robots-sense-their-environment-0723
http://www.nature.com/articles/s41565-018-0194-z
What does this mean for low dose doxycycline use? 40 mg/ day supposedly has no antibiotic effect yet tames the inflammation causing Rosecea ( oradea) or gum disease (periostat). Several studies show that low dose doxycycline is a powerful inhibitor of Matrix Metalloproteinases (MMPs). Mmp's breakdown collagen and elastin so low dose doxy has been studied to slow skin aging. This study uses doxycycline to age the rats skin! Perhaps it's the higher dose but the info in the link below has me worried as it says even low dose hurts mitochondrial function. If mitocondial disfunction causes skin aging, do we want to continue knocking down those MMP's with low dose doxy? To make things worse, another article says metformin can harm mitochondria because it Inhibits oxidative-phosphorylation; enhanced glycolysis ( second link)
Comments appreciated!
https://www.the-scientist.com/daily-news/widely-used-antibiotics-affect-mitochondria-35794
http://www.mitoaction.org/files/Mito%20Toxins_0.pdf
Once again Reason is right:
Late 2018 study concludes "Mutations of mitochondrial DNA are not major contributors to aging of fruit flies" and "Only an artificially induced, very drastic increase of the mtDNA mutation load will lead to reduced lifespan"
"https://www.pnas.org/content/115/41/E9620