How Exercise Repairs Ageing DNA

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Our DNA is constantly exposed to many sources of damage, both from outside the body (such as background radiation and occasional exposure to toxic compounds) and from within (the reactive compounds produced as a byproduct of normal metabolic processes). Cells constantly work to repair DNA damage, but this process isn’t perfect and becomes less and less effective with age, meaning that genetic mutations inevitably accumulate throughout life.

Upon hearing the word ‘mutation’, most people think of cancer or genetic diseases, but DNA damage doesn’t need to cause disease in order to be harmful. Genetic mutations can cause over- or under-production of specific proteins, or they may change the shape of the associated protein in such a way that it no longer functions as well as it should. The impact of such mutations are negligible in a single cell, but over many cells their effects add up. Cells divide and pass on their mutations, and eventually a large proportion of cells within a given tissue are not functioning as well as they should due to accumulated DNA damage.

This damage isn’t restricted to the nuclear DNA (the 23 chromosome pairs in the cell nucleus that make up the human genome), but also affects mitochondrial DNA (mtDNA). This DNA is contained within the mitochondria, the cell’s ‘power plants’, and is particularly vulnerable to damage. mtDNA mutations also have a significant impact on cellular function because they cause mitochondria to become dysfunctional, making them less efficient at powering the cell and resulting in the production of harmful metabolic byproducts. Again, these faulty mitochondria are passed on when cells divide and become increasingly widespread with age.

Can DNA Damage Be Prevented or Reversed?

How can we stop DNA damage? It may eventually be possible to artificially enhance the cell’s existing DNA repair pathways to the extent that almost all damage is negated, but that’s not on the table just yet. Some damage can be prevented by avoiding the things that cause it – for example, staying out of the sun to reduce exposure to ultraviolet radiation, or avoiding chemicals that are known to damage DNA like cigarette smoke and various environmental pollutants. However, some damage is unavoidable, as it is the result of DNA copying errors or damage by reactive molecules produced within the body as part of normal metabolic processes.

Physical exercise produces large amounts of DNA-damaging molecules called reactive oxygen species (ROS). Yet seemingly paradoxically, physical exercise is associated with protection against DNA damage. Outside of extremely intense activity, the damage inflicted by physical exercise appears to be outweighed by compensatory protective mechanisms that activate in response. However, not much is known about how exactly this initial damage and subsequent compensation occurs. That brings us to this review article published in Frontiers in Genetics, which aims to bring together what we know so far about the link between exercise, DNA damage and repair, with a specific focus on sarcopenia. Sarcopenia is the age-related loss of skeletal muscle mass and function, a condition that significantly reduces quality of life in the elderly and in which DNA damage is thought to play an important role.

Why Skeletal Muscle?

Muscle is particularly susceptible to DNA damage for a few reasons. Even at rest, muscle tissue consumes a lot of energy, which means it produces a lot of those damaging ROS. Furthermore, muscle fibres don’t get replaced very often. In cells that have a high turnover rate, such as the cells lining the gut, DNA damage is usually inconsequential. This is because such cells are constantly dying and being shed from the lining, while a pool of stem cells deeper within the gut wall generates replacements. DNA damage occurring in those stem cells is far more harmful, and so evolution appears to have prioritised DNA repair in cells that divide. By contrast, muscle fibres do not divide, but are also rarely replaced, which means DNA damage is mostly there to stay. This damage then causes various problems, but most notably reduces the cell’s ability to synthesise proteins, which is of course essential for maintaining muscle function, and harms mitochondrial function, reducing their ability to power the muscle.

While muscle tissue seems to be more vulnerable to DNA damage, it also benefits greatly from exercise since it is, for obvious reasons, the site for many of the beneficial adaptations that occur in response to physical activity. But how, exactly, do those adaptations work to prevent DNA damage?

How A Single Bout Of Exercise Affects DNA Repair

First let’s look at how a ‘one off’ bout of physical activity affects the muscle. A single bout of exercise results in important temporary changes inside muscle cells:

• The availability of ATP, the cell’s ‘energy currency’ that is produced by the mitochondria, declines because it is being consumed in order to make the muscle contract.
• Because mitochondria are producing ATP at a more rapid rate, they also produce more ROS as a byproduct.
• ROS damages DNA and other cell components, which leads to an increase in specific damaged molecules that are not usually present within cells at high levels.

All of these changes act as signals that tell a cell that it is under significant stress and that its DNA is being damaged. The cell immediately responds to these signals through changes in gene activity, resulting in enhanced stress resistance. Production of anti-oxidants (molecules that neutralise ROS by reacting with them) is increased and systems for repairing damaged DNA are engaged. Damage also activates a wider range of repair systems that are necessary for the longer-term increase in muscle function that comes with exercise. As we’ll see, these changes last beyond the point at which all damage has been resolved (usually after 1-3 days). Thus, even thought physical exercise initially damages DNA, the net effect is positive.

This ‘overshooting’ of the adaptive response to a harmful stimulus has a name: hormesis. Hormesis appears to occur with many types of stimuli such as radiation and temperature extremes but, crucially, it only works when the initial damage is below a certain level. Spending time in the sauna seems to have some health benefits, but you wouldn’t want to be locked in there. Likewise, too much exercise in one go can overwhelm the cell’s defensive mechanisms. There’s presumably an intensity and duration of exercise that ‘optimally’ enhances DNA repair without causing lasting damage, but we unfortunately don’t know what it is. We do know that the relationship between exercise and many health benefits generally follows a ‘U-shaped’ relationship.

Long-Term Effects

To measure resilience against DNA damage, scientists can sample a person’s cells (usually white blood cells), expose them to radiation and observe how they respond to the resulting damage. Such studies have repeatedly shown that the cells of exercise-trained individuals are better at repairing DNA damage than those of untrained people, thanks to increased production of DNA repair enzymes. These studies even show that mitochondria take up these repair enzymes at a greater rate, resulting in faster repair of mtDNA. It therefore seems as though repeated physical exercise is associated with lasting resistance to DNA damage that extends beyond muscle tissue.

This means that even when at rest, past routine exercise is probably protecting you against two of the primary drivers of ageing: DNA damage and mitochondrial dysfunction. This may be an underappreciated component of how exercise protects against age-related diseases like sarcopenia. In addition to the effects that are easy to measure (such as cardiovascular benefits) it may also be slowing ageing at a more fundamental level.

Stem Cells

One aspect of muscle ageing that we haven’t talked about yet is stem cell exhaustion. Though we mentioned that muscle fibres are long-lived and not regularly replaced, muscle stem cells (the cells able to give rise to new muscle cells) still play an essential role. These cells (called satellite cells) divide when muscle tissue is damaged, helping to repair and strengthen it by generating new muscle tissue. While these satellite cells may not contract, they are still exposed to ROS produced within the muscle and sustain DNA damage, which over time can cause them to become senescent, meaning that they are unable to divide. For a cell whose main purpose is to divide to produce new cells, this is a serious problem and is a major contributor to sarcopenia. As muscles age, they become unable to grow in response to exercise or even to keep up with the rate of damage.

Regular exercise cannot fully prevent satellite cells from becoming senescent, but it does appear to protect them from DNA damage and thereby delay senescence significantly. By making muscle cells better at neutralising ROS as they are produced, satellite cells are indirectly protected from damage. Similarly to what was observed in white blood cells, there may also be changes inside the satellite cells that make them better at resisting DNA damage.

Practical Implications

Exercise seems to be good for your DNA, but are there any more specific lessons we can take away from this research, such as what kinds of exercise might be better for enhancing DNA repair? Unfortunately, the answer is not really. We still don’t know how different intensities, duration and types of exercise affect DNA repair mechanisms. There are many different mechanisms for repairing various types of DNA damage, and it is possible that different types of exercise activate some more than others. For example, resistance training produces a lot more muscle damage (and subsequently more muscle growth) than aerobic exercise. Does this translate to specific types of DNA damage and repair? It seems plausible, but more research will be needed to determine this. In the meantime, it might be advisable to engage in a mix of different types of physical activity.