Telomere Length and Mitochondrial DNA Copy Number Over the Mouse Lifespan

The science of intervention in aging has reached the point at which the research community should be undertaking a great deal more of the sort of work exhibited here. The authors of this open access paper have done the public service of producing reference data on telomere length and mitochondrial DNA copy number in multiple tissues over the mouse life span. Telomere length is a terrible metric for aging when measured in the immune cells taken from a blood sample; it varies widely between individuals, is dynamic for a given individual, dependent on day to day environmental and health factors, and trends with age only show up in statistical analyses carried out across sizable study populations – and sometimes not even then. Mitochondrial DNA copy number is more interesting, and a reference work here might be quite useful.

Both of these metrics, regardless of their quality or lack of same, are downstream consequences of lower-level forms of damage in aging. Average telomere length is a loose measure of stem cell activity, a proxy for the replacement rate for cells in a tissue. Stem cell activity declines with age, and thus so does the supply of new cells with long telomeres. Mitochondrial DNA copy number is generally thought to fall with age (though see the results below), and lower copy number counts correlate with poor health outcomes. Mitochondria, the power plants of the cell, undergo a general malaise with age, their function faltering, and this contributes to many age-related conditions, particularly in energy-hungry tissues like muscles and the brain. These processes have underlying causes, and go on to cause further issues themselves. A good fraction of the research community involved in aging seeks to override these evident declines without trying to address the root causes – an approach that may well produce some benefits, but will not solve the problem of aging in and of itself.

Our study aimed to provide chronological aging standard curves and slopes of telomere length and mitochondrial DNA copy number (mtDNAcn), which can help researchers objectively assess the degree of aging in target tissues in various studies using C57BL/6 male mice. C57BL/6 is one of the commonly used rodent models. To evaluate telomere length by qPCR, we used the telomere primer set telg and telc. Unlike previously suggested primers that generate PCR products of various lengths, the telg and telc set produced PCR products of constant length, resulting in stable amplification and clear chronological standard curves.

The telomere qPCR conditions proposed in this study resulted in reproducible and discriminating amplification outcomes, and the fidelity of the qPCR result was further confirmed by telomere restriction fragment (TRF) analysis. The telomere standard curves also showed significant changes with aging. To the best of our knowledge, this is the first report of the aging standard curves of mouse telomeres using the telg and telc set and integrating various tissues across the body.

All 12 tissues showed age-dependent changes in telomere length or mtDNAcn, indicating that we can estimate tissue-specific aging status using at least one of these aging markers. A variety of studies have indicated that telomere erosion occurs in aged human or animal subjects. In our study, all tissues showed telomere length decline with aging. However, the mtDNAcn showed a tendency to increase or decrease with aging depending on the tissue. We found increments in mtDNAcn in the retina, thoracic aorta, and spleen, but the other tissues showed a decreasing tendency with aging.

In addition to mitochondrial dysfunction due to a decreased mitochondrial genome, increased mtDNAcn has also been suggested to be detrimental to cells and eventually induces cellular senescence or apoptosis. Accumulation of mtDNA mutations induces high mtDNAcn in nucleoids (mtDNA-protein complexes), and results in nucleoid enlargement and subsequent mitochondria functional deficiency. Excessive mtDNA replication could be triggered by the activation of twinkle mtDNA helicase and mitochondrial transcription factor A. These previous studies support the notion that an increase in mtDNAcn is a normal phenomenon in aging, although the mechanism of tissue-specific increase or decrease with aging remains to be elucidated.

It is known that telomerase activity in adult tissues differs between human and rodents. Telomerase is constitutively expressed in various tissues of laboratory mice, whereas it is tightly regulated in human somatic cells. Therefore, the results of mouse experiments cannot be directly applied to humans. Nevertheless, animal model experiments are indispensable to understanding human diseases, and the results have to be compared with human data to infer the clinical symptoms of the human body.


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