ADP Sensitivity in Muscle Mitochondria Declines with Age Independently of Fitness
The research here notes an aspect of mitochondrial biochemistry that declines with age in a way that appears unaffected by fitness and exercise. One of the challenges inherent in investigating the mechanisms of aging in muscle tissue is determining the difference between decline due to disuse (secondary aging) versus decline due to intrinsic processes of damage accumulation (primary aging). We live in a world in which being older tends to mean being wealthier, with greater access to transportation and calories. Near all older adults fail to maintain a good program of exercise and diet, and the difference between those who make the effort to remain fit and slim and those who do not is sizable. That much is demonstrated by the significant gains in cardiovascular health and muscle strength that can be achieved in the elderly through structured exercise programs. So it is interesting to see research results in which the data makes it very clear that a specific measure of aging in muscle tissue is independent of exercise.
Aging is a complex process associated with skeletal muscle and strength loss as well as insulin resistance. The cellular mechanisms causing muscular and/or metabolic dysfunction with aging remain poorly understood. However, one proposed mechanism of action driving the aging process is an increase in mitochondrial-derived reactive oxygen species (ROS). Specifically, increased ROS emission has been associated with motor unit loss and abnormal morphology, muscle fiber atrophy, insulin resistance, inflammation, and apoptosis. Conversely, transgenic and pharmacological approaches that attenuate mitochondrial ROS have been shown to preserve insulin sensitivity, mitochondrial content, and muscle mass in diverse models while also prolonging lifespan. Altogether, these data implicate mitochondrial ROS as a fundamental mechanism of action influencing the aging phenotype.
Although these elegant rodent models provide compelling evidence to link mitochondrial ROS with age-associated pathologies, the data in humans remain ambiguous. Contradictory findings suggest that either mitochondria are not responsible for the increased oxidative stress with aging or, alternatively, contemporary in vitro assessment of mitochondrial ROS emission does not accurately reflect in vivo responses. ADP transport is a highly regulated process that is attenuated with rodent models of insulin resistance and improved following high-intensity exercise. Moreover, there is indirect evidence to suggest that the protein required for ADP transport into mitochondria, adenine nucleotide translocase (ANT), is impaired with aging in housefly and rat skeletal muscle. Therefore, previous assessments of mitochondrial ROS emission in the absence of ADP may not adequately reflect the in vivo environment, and as a result current data from human skeletal muscle may underestimate the importance of mitochondrial ROS in the aging process.
In the present study we re-evaluated mitochondrial bioenergetics by establishing a protocol in permeabilized muscle fibers to simultaneously examine mitochondrial respiration and hydrogen peroxide (H2O2) emission in the presence of various substrates and ADP concentrations. Using this in vitro protocol, we assessed age-related mitochondrial defects by comparing healthy young males to healthy older males. We also examined whether potential age-related defects in mitochondrial bioenergetics could be improved over 12 weeks of resistance exercise training. We provide compelling evidence that although the capacity for mitochondrial ROS emission is not increased with aging, mitochondrial ADP sensitivity is impaired, such that mitochondrial ROS, and the fraction of electron leak to ROS, are increased in the presence of virtually all ADP concentrations examined. In addition, although resistance-type exercise training improved several aspects of muscle health in older individuals, the fraction of electron leak to ROS, mitochondrial H2O2 emission rates in the presence of ADP, and muscle oxidative stress were unaltered, suggesting an increase in mitochondrial ROS accompanies the aging process.
Altogether, the assessment of mitochondrial bioenergetics in the presence of sub-saturating ADP concentrations has revealed that there are age-associated impairments in mitochondrial bioenergetics, which are not fully recovered with prolonged resistance-type exercise training. The mechanism for the attenuation in ADP sensitivity remains unknown, but oxidative damage has been proposed as a likely explanation. Regardless of this knowledge gap, the present data imply that an increase in mitochondrial ROS is associated with the primary aging process. Moreover, despite the inability of resistance training to rectify age-related mitochondrial ROS emission, older individuals experienced favorable changes in muscle mass, strength, and fat mass, reinforcing the importance of a physically active lifestyle throughout the lifespan.
The first paragraph of the Quote for this article points out that the driving force in muscle aging and metabolism is an increase in mitochondrial-derived reactive oxygen species (ROS). The main control of ROS in skeletal muscle mitochondria is the UPC3 gene (uncoupling protein 3), which is activated by superoxide within the mitochondria. The important gene SNP for the UCP3 gene is rs1800849, with T being the good allele. Being homozygous for the TT alleles protects your mitochondria against excessive ROS by uncoupling and releasing heat to the cytosol, thereby protecting the mitochondria membranes from superoxide and other ROS species. This is a longevity SNP and protects the skeletal muscle from muscle wasting with age. A Danish study found centenarians with the UPC3 TT alleles have the highest hand grip strength which is the best measure of muscle wasting in the elderly. I happen to be homozygous for the TT alleles.
@biotechy "This is a longevity SNP " can you proove it?
@Dv: The best reference I can give you for the longevity benefits of UCP2, UCP3, and UCP4 is as follows: Rose, 2011 Plos One Further support of the Uncoupling Theory of Aging.
Biotechy, will you kindly share how you obtained all of your personal genotype information, so that I can obtain the same information about myself?
@NY2LA: I got a 23andme DNA genome kit that gives you your Raw DNA Data Base for about half a million SNP's. Then I had it analyzed by Promethease for $5 to give me a listing of my worst gene SNP's with associated diseases discussed, and a listing of my best gene SNP's with discussion and references of why they ate good. Then I started using SNPedia (an online encyclopedia of SNP data). SNPedia gives you all the research references for each SNP that is implicated in diseases, and much, much more on the alleles involved, and which allele is associated with one or more or many diseases. I put my SNP numbers in a notebook, along with the alleles I have, and the disease risk I have if any. SNPedia also gives info on geographic distribution of each allele, gene to which the SNP belongs, and much more. In my notebook list I put my alleles in after the SNP number with a red pen. Before the SNP number I put the gene name, and before that, I put the frequency % of the alleles I possess. After my alleles I enter disease risks an other info. I put a red + sign over the good allele, and a red - sign over the bad allele. For the bad alleles that are not my own, I place a black minus sign, and a black plus sign over good alleles that are not my own. This notebook system works good for me.
PS: It is also useful and efficient to group your SNP's according to traits or diseases such as AD, Heart disease, breast cancer if female, prostate cancer if male, inflammation, vitamin related, longevity or aging, etc. To save space I never write rs before the SNP number as that is the same for all SNP's.
Thank you, biotechy. I may try it. For the past few days, I've been seeing reports on a high error rate, though. Are you concerned about that?
ttps://www.nature.com/articles/gim201838
https://www.nature.com/articles/gim201838
There are a number of factors that go into the degree of accuracy that is possible, and various companies may use different analysis systems with different degrees of accuracies. I have also tested my genome with Veritas Genetics, and not noticed any differences in the testing results from my 23andme results, thus I am not concerned. If I had a cancer or something like that, I would probably get an individual test for that by Veritas Genetics or some company like that which specializes in specific gene testing for diseases in addition to full genome testing.
@NY2LA: Looking further at the probable source of your high error rate article, it should be noted that some companies report SNP variant results from a mixture of alleles on the DNA strand and matching RNA strand. If that is the case, when you go to SNPedia for your SNP number, if the reporting company used the RNA strand, it will have the reverse alleles as the unreported DNA strand. After I enter my alleles in my notebook, I check to see what strand 23andme used, and if they used the RNA strand for my alleles. I put a {R) after my red allele to designate that if I want to use only DNA strand allele, I must reverse the allele letters to conform with SNPedia alleles and most reference reports. Thus, the A allele becomes the T allele and the C allele becomes the G allele in the opposite DNA strand.
Biotechy, sounds good. I've actually already had my full genome sequenced by Human Longevity, Inc, and they provided a 70 plus page report. I am interested in comparing reports from different companies though, too.
NY2LA: WOW, a 70 plus page report, That's impressive. For my Veritas Genetics genome analysis, I submitted all my grandparents and parents age at death and cause, and had a 1 hour phone interview with the geneticist. I had a fairly boring report that I can visit online anytime. I had only 1 mutation that I have a 1 in 2000 chance of my offspring getting if I had married someone with the disease (Tar disease), so it really amounted to nothing. My 23andme report and Promethease report came up with about a dozen gene mutations of a Magnitude 3.0 and many many more of good or bad repute of lesser Magnitude. I had about 20 longevity genes SNP's, like FOXO3A (4), APOE2 and P53 among them. I know you can access several Promethease reports online and summaries of 23andme reports as well.
In my notebook of SNP's that I developed from my 23andme raw DNA data I use the format I explained above. If I have no raw DNA data results for the SNP number I am looking for I enter an N after the SNP number. That saves me from trying to track the SNP number again in the future. If there is no discussion info on the SNP number I enter an ND after the alleles. If I am homozygous for the good SNP alleles I put a solid but small black circle in front of the SNP number, if I am homozygous for the bad allele, I put a small red circle in front of the SNP number; if I am heterozygous and there appears to be SNPedia info that this confers some benefits, I put an open black circle in front of the SNP number, and if the heterozygous condition confers some bad did-benefits, I put a red open circle in front of the SNP number.