DNA damage and repair capacity related to diet and exercise: a new dimension in cancer treatment?

DNA damage is recognised as the first step in the development of cancer, but also many other chronical diseases as well as the aging process. Oxidative stress and inflammation are closely intertwined in disease pathogenesis [1]. Oxidative stress is characterized by an imbalance between formation of reactive oxygen species (ROS) and antioxidant defense mechanisms, induced by endogenous and exogeneous factors [2]. Most chemotherapeutics generate ROS in cancer cells which causes DNA damage and trigger cell death. Unfortunately, they also damage healthy cells [3]. Increasing evidence indicate that dietary factors and exercise affect DNA stability by upregulating antioxidant defense system and modulating repair capacity (Figure 1).

Figure 1. Formation of reactive oxygen spices (ROS): DNA damaging agents. ROS are highly reactive chemicals formed from O2, and cells are continuously exposed to both endogenous and exogenous sources of ROS. At high level, ROS may lead to DNA damage and genetic mutations that activate carcinogenesis as well as other chronical diseases. The defense system consists of 1) Antioxidant defense system – the first line of defense, 2) DNA repair mechanisms – the second line of the defense and, 3) Apoptosis (programmed cell dead) – the third line of defense [4]. Diet and exercise may protect against DNA damage

Why should diet and exercise be used as a part of a cancer treatment regimen?
In recent decades, progress in early detection and treatment of cancer has led to an increase in cancer survivors, defined as all people who have been diagnosed with cancer, including before, during and after treatment. Treatment regimes in cancer patients are intended to stop cancer progression but also prolong patients’ survival and reduce the risk for relapse [5]. In addition, there is an intention to reduce the negative side effects of cancer therapy which many cancer patients are struggling with years after treatment.
A large number of bioactive compounds has been identified in plant food (e.g. whole grains, berries, spices, nuts, coffee, specific fruit and vegetables) with the potential of dampening oxidative stress and inflammation [6-10]. These compounds provides a protection against DNA damage via different modes of action, including increased resistance to oxidative damage and induction of alterations of DNA-repair processes [11]. In numerous clinical trials, antioxidant-rich foods and beverages have resulted in reduced DNA damage, a higher antioxidant capacity and increased DNA repair capacity [12-16]. This indicate that a prudent diet rich in specific plant-foods may be beneficial for cancer survivors, especially individuals with molecular signatures creating major oxidative stress and inflammation.

Acute exercise contributes to a transient increased production of ROS due to an increased activity in the mitochondria and other metabolic pathways, which in turn may lead to oxidative stress and DNA damage [17]. The increase in ROS will depend on the characteristics of the exercise, such as intensity, time, and frequency [18]. However, it seems that DNA repair likely occurs within a least 3 days [17]. Importantly, regular exercise has been shown to up-regulate the antioxidant defense system and enhance DNA repair processes [19]. On the other hand, very high levels of activity may led to DNA damage, and it has therefore been proposed that the relationship between exercise, ROS and DNA damage may follow a U-shaped curve [19]:

  • Inactivity results in higher risk of DNA damage
  • Moderate/regular exercise may protect against DNA damage
  • High exercise/overtraining may increase DNA damage

However, it is unclear where the threshold limit exists between the beneficial effects of regular exercise level and the point of overtraining associated with higher oxidative damage and insufficient DNA repair. Considering this, regular exercise and aerobic exercise in particular may contribute to reduced DNA damage due to a higher antioxidant capacity and increased DNA repair capacity.

Disease outcomes and survival
Dietary factor’s and exercise’ ability to modulate DNA stability adds a new dimension to the mechanisms linking diet, physical activity and cancer. There is strong evidence for the role that diet and physical activity play in cancer prevention, but the relations to disease outcome and survival is less studied [20].

Historically, dietary advice to cancer survivors focused on maintaining a persons’ energy intake and micronutrient sufficiency as well as mitigating the effects of unintentional weight change, loss of muscle mass, nausea, and gastrointestinal toxicity. The question now is whether we also should focus on foods and drinks that have been suggested to dampen oxidative stress and inflammation, which in turn may protect against DNA damage. Antioxidant-rich foods and drinks can boost the antioxidant defense system, moreover, there are indications that it will enhance DNA repair capacity. Both mechanisms can theoretically increase treatment tolerance, reduce risk of recurrence, and reduce long-term side effects in cancer patients.

Physical activity has emerged as an important factor to improve cancer outcomes. There is strong evidence that physical activity confers diverse benefits related to fatigue, depression, quality in life, physical function, body composition, and cardiorespiratory fitness [21]. In addition, physiological and biological process during and after exercise may also impact the rate of tumor growth and boost the immune system, which in turn may affect therapeutic toxicity and tolerance [22]. In recent years, high intensity interval training (HIIT) has received greater focus in improving physical fitness and health-related outcomes in cancer survivors [23]. In this context, benefit of total physical activity for DNA repair appears to be driven primarily by high intensity exercise [24]. Given that DNA repair counteracts DNA damage, and excessive DNA damage is involved in carcinogenesis, high intensity exercise may be beneficial in order to reduce risk of relapse as well as other chronical diseases in cancer survivors.

Conclusion
Cancer is associated with a DNA instability due to increased damage to DNA. DNA repair capacity is regarded as an indicator of individual cancer susceptibility and growing evidence suggests that DNA repair capacity is an important factor in tolerance to chemotherapeutic agents [25]. Dietary factors and exercise can protect against DNA damage by upregulating antioxidant defense system and modulating repair capacity. However, there is a need for prospective studies that monitor these markers related to diet and exercise which will be of great importance for cancer survivors.

Author and affiliations:
Anne Lene Nordengen, BSc in Sports Biology and MSc in Sports Physiology from The Norwegian School of Sport Sciences. She is currently PhD student at the Department of Sport Science and Physical Education, University of Agder, and is also affiliated with the Department of Nutrition, University of Oslo, and NorGenoTech AS (Oslo Cancer Cluster), Norway.

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