Fight Aging!

Occasionally I'll post research that is only tenuously relevant to aging, but nonetheless fascinating. That is the case for this article and open access paper on a fairly new and still poorly understood area of telomere biology. The researchers link exercise to the generation of TERRA, or telomeric repeat-containing RNA, which might lead to all sorts of speculation among long-time readers here. Exercise, telomere length, and aging are all in the same general bucket of items with many established links. Speculation is all that can be done by onlookers at the present time, however, given that the research community has yet to establish firm connections leading from TERRA to any of the behaviors of telomeres and, separately, exercise that are known to be relevant in aging. Still, reading through gives a good sense of just how complex the situation is under the hood. There are no simple relationships in biochemistry.

Telomeres are repeating DNA sequences that cap the ends of chromosomes. Every time a cell divides a little of the telomere is lost as the cell's DNA is replicated. When the remaining telomeres become too short the cell self-destructs or becomes senescent. This is a part of the Hayflick limit, which has evolved to ensure that most cells can only replicate so many times. Every tissue consisting of such limited cells is supported by a much smaller population of stem cells, which use telomerase to lengthen their telomeres and thus consistently produce an ongoing supply of new cells with long telomeres to replace those that reach their limits. The situation in which only some cells are privileged to divide indefinitely exists because it keeps cancer rates low enough for complex long-lived species to exist and evolve. These days telomere length and telomerase are hot topics in aging research, though not all of it is entirely justified to my eyes. Telomerase gene therapies have been shown to extend life in mice, which may be a result that works along the same lines as stem cell therapies, by increasing the activity of cells and maintenance of tissues. Average telomere length declines with age, but this is a statistical relationship across populations, of limited use for individual diagnosis. Telomere length seems very much like a marker and not a cause of aging.

Telomeres are DNA, and DNA encodes blueprints for proteins. A part of the process of gene expression by which proteins are created is transcription, wherein DNA is used as the pattern to produce RNA molecules. Are telomeres transcribed just like the rest of the nuclear DNA? Yes, as it turns out. Telomeric DNA is transcribed to produce TERRA molecules. What does TERRA do? That is an interesting question with few firm answers at the present time, but a lot of leads and maybes. Telomeres are not just passively sitting there: they encode for RNA, and that RNA does things. By linking TERRA to exercise, known to improve health via a variety of mechanisms, there is the thought that perhaps there are more direct connections than previously thought between changing telomere length and the various options like exercise and calorie restriction known to slow the progression of aging. It is particular interesting, for example, that TERRA may regulate the activity of telomerase, though as for much of the other results relating to TERRA this is fairly tentative and subject to revision. Is this all really relevant to the future of our lives, however? Probably not, as exercise, calorie restriction, and similar ways to modestly slow aging are not the gateways to human rejuvenation. They do too little to address the forms of damage that cause aging, and only repair of that damage, rather than merely slowing it down, can greatly extend life. But that said, this is a most interesting space in the study of cellular biology.

Exercise Boosts Telomere Transcription

When healthy individuals perform a cardiovascular workout, their muscles increase transcription of telomeres. A novel transcription factor appears to promote telomere transcription and provides the first direct evidence that telomere transcription is linked to exercise and metabolism in people. Telomeres were thought to be transcriptionally silent until several years ago when researchers found that mammalian telomeres, including human ones, are readily transcribed into telomeric repeat-containing RNA (TERRA). These RNA molecules have been shown to associate with telomeres but whether and how TERRA can protect telomeres - the repetitive sequences at the ends of linear chromosomes that form a sort of aglet to protect the structures - or promote the lengthening of the ends of chromosomes is not yet fully understood.

Researchers first analyzed human telomeric sequences for potential transcription factor binding sites. The researchers identified a potential binding site for the transcription factor nuclear respiratory factor 1 (NRF1), then confirmed its ability to bind the ends of chromosomes in human cancer cell lines. Because NRF1 is activated when stores of ATP are depleted, as during exercise, the team next enlisted 10 young and healthy volunteers to a low- or high-intensity workout on a stationary bicycle for 45 minutes. The researchers took muscle biopsies and blood samples prior to, right after, and 2.5 hours after the exercise. TERRA levels were increased 2.5 hours after both the low and high intensity workouts and were highest after the high intensity exercise. This is the first evidence that telomeres are transcribed in non-dividing human tissue. Exercise produces reactive oxidative species (ROS) that may damage telomeres. The researchers are now addressing the hypothesis that the TERRA molecules produced from NRF1-dependent telomere transcription may act as scavenger molecules that react with the ROS, protecting the telomere itself from oxidation. "As it is not yet established what role TERRA plays at mammalian telomeres, it is premature to speculate on the effect of NRF1 and TERRA upregulation in exercise on telomere biology or aging."

Nuclear respiratory factor 1 and endurance exercise promote human telomere transcription

DNA breaks activate the DNA damage response and, if left unrepaired, trigger cellular senescence. Telomeres are specialized nucleoprotein structures that protect chromosome ends from persistent DNA damage response activation. Whether protection can be enhanced to counteract the age-dependent decline in telomere integrity is a challenging question. Telomeric repeat-containing RNA (TERRA), which is transcribed from telomeres, emerged as important player in telomere integrity. However, how human telomere transcription is regulated is still largely unknown.

We identify nuclear respiratory factor 1 and peroxisome proliferator-activated receptor γ coactivator 1α as regulators of human telomere transcription. In agreement with an upstream regulation of these factors by adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK), pharmacological activation of AMPK in cancer cell lines or in normal nonproliferating myotubes up-regulated TERRA, thereby linking metabolism to telomere fitness. Cycling endurance exercise, which is associated with AMPK activation, increased TERRA levels in skeletal muscle biopsies obtained from 10 healthy young volunteers. The data support the idea that exercise may protect against aging.