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Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases

aging clonally expanded mtdna mutations ros

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#1 alc

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Posted 09 May 2016 - 11:59 PM


http://www.sciencedi...568163716300599

 

The article is under paywall, but the highlights are:

 

"

Mitochondrial dysfunction in conjunction with altered mitochondrial dynamics drives aging.

Spontaneous errors of replication cause mtDNA point mutations, deletions and depletions.

Clonally expanded mtDNA mutations lead to mitochondrial dysfunction.

ROS does not appear to be a critical factor in aging.

 

"



#2 corb

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Posted 11 May 2016 - 03:17 AM

Aubrey De Grey, December 2006:

 

Superoxide generated adventitiously by the mitochondrial respiratory chain can give rise to much more reactive radicals, resulting in random oxidation of all classes of macromolecules. Harman's 1956 suggestion that this process might drive aging has been a leading strand of biogerontological thinking since the discovery of superoxide dismutase. However, it has become apparent that the many downstream consequences of free radical damage can also be caused by processes not involving oxidation. Moreover, free radicals have been put to use by evolution to such an extent that their wholesale elimination would certainly be fatal. This multiplicity of parallel pathways and side-effects illustrates why attempts to postpone aging by "cleaning up" metabolism will surely fail for the foreseeable future

 

As for the paper posted, I acquired it and was going to paste some interesting quotes from it, but ... there really isn't anything there worth quoting.
Basically the bottom line they present is - lift weights, take your MTOR inhibitors and pray Aubrey gets more funding - it's more or less a direct quote. Lift weights. Take rapamycin. Expect genetic tinkering therapies that might or might not come at some point in your life.

 

I guess I might as well post the conclusion it's the most informative part of the paper:

 

Aging is a multifactorial, progressive, biological process with mitochondria playing a central role. The
MFRTA, once at the forefront of aging theory, has lost favor since its fundamental notion of a “vicious”
cycle of ROS generating ETC disruption, and hence more ROS, is based on anecdotal evidence. This
does not imply that high levels of ROS do not contribute to the aging phenotype through oxidative
damage to cellular components, such as proteins and lipids.

However, ROS does not appear to be the
initiating or critical factor. The theory of mitohormesis states that low levels of ROS are important
signaling molecules that regulate stress response pathways and enhance longevity. Therefore, clonally
expanded mtDNA mutations caused by replication errors leads to mitochondrial dysfunction. It is this
31
process, in conjunction with altered mitochondrial dynamics, that emerges as the driving force behind
aging (Figure 4). Here, we showed that deficiency and/or dysfunction in many of the nuclear-encoded
mtDNA replication proteins, including Polγ, PolG2, Twinkle, TFAM, MGME1 and RNase H1, results in
age-related diseases and/or phenotypes both in vitro and in vivo. Future studies focused on understanding
the mechanisms of action are needed to effectively delay aging and prevent age-related diseases.

 


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