SIRT3 the Guard Against Aging, Cancer and Neurodegeneration

Do you appreciate that increasing NAD+ levels activate sirtuins and want to know more details about the anti-aging benefits associated with this? Then, this is the article for you. You may be familiar with sirtuins and their role as longevity genes, but this article focuses on SIRT3 in particular. SIRT3 has been investigated for almost 20 years due to its role in preventing illnesses such as cancer and neurodegenerative diseases.

It all starts with SIRT3’s activity in the mitochondria...

The Mitochondria Produce the Energy for our Cells

Mitochondria in our cells convert the food we eat to energy that our cells can use (ATP). To do this the mitochondria is in constant communication with the nucleus. The mitochondria are also highly sensitive to environmental changes such as exercise, calorie restriction, and oxidative stress (the creation of damaging products within the cell). This is important as the mitochondria can alter the level of energy production based on the requirements of the body at that time. Overall, as the energy factories of our cells they are vitally important.

SIRT3 Protects Cells from Aging

SIRT3 is involved in the vital ATP production in the mitochondria. Specifically, it is involved in the final stage of energy production called the electron transport chain. This process creates highly reactive versions of oxygen (called reactive oxygen species, ROS) which are highly damaging to the cell. As we age, these reactive oxygen species cause more and more cellular damage and eventually communication between the mitochondria and the nucleus breaks down.

When we are young and have plentiful NAD+ levels the activation of SIRT3 is high. This is important as SIRT3 activates pathways that protect the cell from these reactive oxygen species. These antioxidant pathways mop up all the free radicals preventing any damage.

In older cells with low levels of NAD+ the activation of SIRT3 is also low, making these cells more susceptible to damage. The accumulation of damage to proteins, lipids and DNA contributes to the aging process. Therefore, ensuring levels of NAD+ are maintained as we get older is essential to protecting our cells especially our DNA from damage.

SIRT3 Protects Cells from Cancer Development

SIRT3 controls the expression of genes involved in fat metabolism, protein metabolism, respiration and antioxidant protection. It is located in the mitochondria due to its role in energy production which have been well studied. Research was conducted on mice models and when the SIRT3 gene was removed these mice had increased rates of metabolic defects, cancer and cardiac failure. This suggests that SIRT3 is directly involved in the protection of cells and the removal of damage.

SIRT3’s involvement in cancer development is due to its role in regulating both cell death and cell survival. SIRT3 mediates the protective pathways which are activated in response to different types of cellular stress. As mentioned, the antioxidant pathways deal with highly reactive oxygen species.

Furthermore, SIRT3’s role in normal metabolism helps prevent cancer. In cancerous cells the metabolism is altered. These cells will preferentially use glycolysis (the breakdown of glucose) as an energy source without the rest of the normal pathway. This results in less energy (ATP) production. This is because glycolysis doesn’t require oxygen to be present, but cancer cells will do this even if oxygen is present. This alteration allows cancerous cells to survive in unfavorable conditions such as hypoxic environments (lack of oxygen).

SIRT3 Protects Neurons from Degrading

The main cause of many neurodegenerative diseases still remains unknown. These diseases also have no curative treatments available resulting from the lack of knowledge about their development. One thing that is well established is that neurons require large amounts of ATP to function and the mitochondria are their main source of energy. As we age the increased levels of reactive oxygen species cause mitochondrial dysfunction, which can contribute to neuron damage.

Testing in animal models of Alzheimer’s disease showed that calorie restriction reduced the progressive neuronal damage. It is thought that this protection is via the activation of SIRT3. Further studies increased the expression of SIRT3 in these models resulting in a significant increase in neuronal lifespan. The neuroprotective function of SIRT3 fits with its role in maintaining optimal mitochondrial function and the activation of antioxidant pathways.

The correlation between the development of age-related diseases and the decline in levels of NAD+ is no accident. NAD+ is essential for cells to survive. The main effector of NAD+ are sirtuins. These longevity genes have so many protective functions that are pivotal to preventing disease. SIRT3 has been a focus because of its protection against aging, cancer and neurodegeneration. So, to ensure that your cells are best equipped to protect themselves from damage it is essential to maintain sirtuin levels and NAD+ levels.

Learn more about NAD and aging research in mice.

Learn more about the mitochondria: the key component to aging.

References;

• Kincaid, B., & Bossy-Wetzel, E. (2013). Forever young: SIRT3 a shield against mitochondrial meltdown, aging, and neurodegeneration. Frontiers in aging neuroscience, 5, 48.