The Other Harm Caused by Mitochondrial DNA Damage in Aging

As I'm sure you all know by now, mitochondria are swarming powerplants within the cell, descendants of symbiotic bacteria that bear their own DNA separate from the DNA in the cell nucleus. Mitochondrial DNA provides the blueprints for proteins making up the machinery of a mitochondrion, but it isn't as well protected or as well repaired as nuclear DNA. Given that a lot of reactive compounds are funneled through mitochondria in the processes that keep a cell powered, it is only to be expected that mitochondrial DNA becomes progressively more damaged over time. The range of mechanisms that have evolved to deal with that damage cannot keep up over the long term, and as a result a small but significant portion of our cells fall into ruin on the way to old age, becoming populated by dysfunctional, damaged mitochondria, and causing a great deal of harm to surround tissues and bodily systems by exporting a flood of reactive biochemicals. You can read a longer and more detailed description of this process back in the Fight Aging! archives.

So that is one side of the issue of mitochondrial DNA damage and its contribution to degenerative aging - and that in and of itself would be more than enough to make mitochondrial repair biotechnologies a research priority. There are many different potential ways of fixing or rendering irrelevant mitochondrial DNA damage, and allowing mitochondria to continue to function as well as they did at birth for an indefinite period of time. The sooner one of them is developed into a working therapy the better.

In considering mitochondrial damage there is another, more straightforward process at work, however. Many types of cell normally operate fairly close to the limit of the power provided by their mitochondria, including important cell populations in the brain and nervous system. As mitochondrial DNA damage accumulates with age, power production - meaning the pace at which adenosine triphosphate (ATP) is produced - falls off and cells either die or malfunction far more often than they did in youth. This is outlined in a recent open access review paper:

In aerobic cells the majority of ATP is produced by oxidative phosphorylation. This process takes place in the mitochondria where electrons that are donated from the Krebs cycle are passed through the four complexes (complex I-IV) comprising the electron transport chain (ETC), eventually reducing oxygen and producing water.

...

Many cells operate at a basal level that only requires a part of their total bioenergetic capability. The difference between ATP produced by oxidative phosphorylation at basal and that at maximal activity is termed "spare respiratory capacity" or "reserve respiratory capacity" ... Under certain conditions a tissue can require a sudden burst of additional cellular energy in response to stress or increased workload. If the reserve respiratory capacity of the cells is not sufficient to provide the required ATP affected cells risk being driven into senescence or cell death.

...

In this paper we hypothesize that mitochondria contributes to aging and age-related pathologies through a life-long continued decrease of the respiratory reserve capacity. The decrease sensitizes high energy requiring tissues to an exhaustion of the reserve respiratory capacity. This increases the risk of a range of pathologies that correspondingly are known to be age-related. Through a review of the effects of aging on the regulation of oxidative phosphorylation, we wish to substantiate this hypothesis. In addition, by using brain, heart, and skeletal muscle as examples, we will review how an age-related decrease of the reserve respiratory capacity is implicated in a variety of pathologies in the affected tissues.

Interestingly, there is a good case for arguing that it isn't just damage to mitochondria DNA (mtDNA) that reduces levels of power production in a cell's mitochondria - there are other changes taking place that turn down the dial, which in the absence of more definitive knowledge as to their causes could be classified either as programmed aging or as a programmed response to stochastic damage in other cellular systems:

Cumulative damage to the mtDNA is however, not the only contributor to the age-related decline of oxidative phosphorylation. Transcriptional profiling has revealed different regulation of nuclear genes encoding important peptides for oxidative phosphorylation when comparing young to old.

Either way, those mitochondria still need fixing. The biotechnologies capable of that job are on the horizon, and would be coming closer more rapidly if those involved in the work had a greater level of funding.

Comments

Even assuming it becomes possible to biosynthesize in vitro and then introduce cells with rejuvenated mitochondria, would an aged human body be able to withstand the flood of energy? Would the increased energy allow the body to rejuvenate itself to some extent?
Researchers, the first significant evidence of successful rejuvenation will open the floodgates to billions of taxpayers dollars to fund your research. For now, however, people remain skeptical or ignorant of your efforts.

Posted by: PacRim Jim at July 2nd, 2012 3:43 PM

Lay readers, as myself, typically, I guess, relate information such as this to their own case as they seek understanding. In my case, I am a 75 year old cancer survivor (esophagectomy), haemochromatosis, pacemaker powered, chemo and radiation ravaged old guy. Nevertheless, my various doctors advise me that I am an outlier for my age regarding activity, physical fitness (regular weight lifting at gym) mental alertness and overall activity level, including competitive pistol shooting at moving and changing target scenarios against young people. Mentally active, I'm a retired academic, PhD economist and yet active author.
All this tiring comment leads me to speculate - in the case of your research - that (1) an assumed genetic (?) outlier like me might be a likely candidate for robust effects from application of any discovered therapy and (2) perhaps, for some reason, my make up may contain a cell profile or cell characteristic pattern that exhibits less than normal deterioration over time for reasons that you seek in your research.

Posted by: gunnar myrdal at July 2nd, 2012 4:27 PM

This leads me back to a favorite speculation of mine...
If one were to take a tissue sample of a person, extract the stem cells and graft them with superior Mitochondria (say, bird derived), expand the tissue sample reasonably and then apply that systemically... what would the perfusion rate be? Would it be reasonable to expect the upgraded stem cells to do as they seem to do namely by donating mitochondria to needy cells and would the superior mitochondria slowly percolate to most cells in need and provide the boost for proper functioning and ultimately take over?

btw: how about upgrading the RSS feed to allow proper inclusion in social media? I always hand edit the item when i post it to

https://plus.google.com/b/115173252791859690613/115173252791859690613/posts

Posted by: Curious at July 15th, 2012 4:28 AM
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