Why energy levels decline with age?

Highlights 

• Energy levels decline with age due to declining levels of cellular NAD+ 
• NAD acts as an electron transporter and is essential to cellular energy production  
• NAD+ is required for sirtuin activation which maintains mitochondrial health
  

Introduction

Aging is commonly associated with feelings of tiredness and fatigue. This can be attributed to declining NAD+ levels within our cells as we age. NAD+ has many roles within our cells but one of the most important is its role in energy production. This article will describe how NAD+ is involved in energy production and how declining NAD+ levels contribute to age related energy decline. 

NAD+ is vital for energy production

As we get older, we may begin to feel less energised. This is because the decline in our cellular NAD+ levels reduce our cells ability to make energy. 

NAD+ is a cofactor involved in over 500 reactions within our cells. This means it is a non-protein molecule that supports the enzymes involved in these reactions. NAD+ is particularly important for metabolic pathways, due to its role in redox reactions. These reactions involve the transfer of electrons from one molecule to another and are vital to make ATP, the cells energy currency (1).

It is well understood that as we age our NAD+ levels decline, this is a result of several changes within our cells but one of the main impacts this has on our bodies is a reduced ability to manufacture ATP.  

Metabolism is the collection of reactions by which our cells make ATP from the food we eat. It involves a multitude of complex processes involving many enzymes and reactions but the main stages are;

• Glycolysis 
• The citric acid cycle (also called the Krebs Cycle)
• The electron transport chain

NAD+ is essential to each of these stages. With each stage using oxidation reactions, that involves the removal of electrons. It is the job of NAD as an electron transporter to harness the electrons and take them to the mitochondria for the electron transport chain to use them in creating ATP. 

Therefore, anything that alters NAD+ production (such as aging) will directly influence energy production in our bodies. This idea is further supported by the compartmentalisation of NAD+ levels within the cell. Levels of NAD+ are considerably higher in the mitochondria than anywhere else in the cell reflecting the importance of NAD+ in energy production (2).

The two forms of NAD: NAD+/NADH

NAD+ is directly involved in metabolic processes that the body uses to make energy. It does so because it assists in carrying electrons from one molecule to another. NAD+ can do this by changing its structure slightly when required.

Within our cells NAD is constantly changing between NAD+ and NADH. The name and structure of NAD changes as it drops of and picks up electrons. 

Think of NAD as a bus picking up and dropping off electrons at different places in the cell. NAD+ is called the oxidised form, and in this state, it accepts electrons from other molecules (like an empty bus ready to pick up passengers). 

When NAD+ accepts 2 electron and a hydrogen molecule (H+) it becomes the reduced form NADH. In this state the bus is full, and it is ready to transport the passengers (the electrons) and drop them of at the desired location. As electrons are negatively charged the two positive charges for the NAD+ an H+ are cancelled out by the two negatively charged electrons, resulting in NADH which is neutral and therefore has no ‘+’ (3).

Once the NADH (that is loaded with electrons) reaches the electron transport chain (in the inner mitochondrial membrane) it donates the electrons and is oxidised back to NAD+. This helps establish the electrochemical gradient needed to power ATP synthesis. Ultimately ATP production is dependant on NAD to occur (4). Which is why declining NAD+ is detrimental to our energy levels. 

Mitochondrial health declines with age

Maintaining NAD+ levels are important to ensure optimal energy production as we age but another factor is maintaining our mitochondrial health. Our mitochondria are often called the powerhouse of the cell. They have this title because they are the site of energy production in our cells. Therefore, ensuring they are functioning optimally is vital. 

Just like every other part of our cells our mitochondria are susceptible to damage, and research has shown that our mitochondria not only become less efficient at producing energy, but the number of mitochondria in our cells declines with age. With mitochondrial dysfunction being established as a key hallmark of aging (5).

The mitochondria are highly dynamic organelles that form networks which can change size, shape, and mass. Each cell can contain hundreds and thousands of mitochondria. If the cell is very active such as in the brain, heart, liver and muscle cells then the number of mitochondria is generally higher. Furthermore, they are highly sensitive to environmental stress such as exercise, calorie restriction, and oxidative stress (the creation of damaging products within the cell).

Additionally, mitochondria cannot simply be replaced when they are damaged, because mitochondria evolved from bacteria, they contain circular DNA (compared to the linear chromosomes in human DNA), so new mitochondria can only be made from existing mitochondria within our cells. 

Our mitochondria are vital to energy production as well as various other key cellular processes so ensuring they remain healthy and working efficiently is essential to maintain energy levels as we age. 

Sirtuins support mitochondrial health

As part of its function NAD+ acts as a signalling molecule to switch on other cellular pathways one of which is the sirtuins. Sirtuins are a family of proteins (SIRT1 – SIRT7) that are also found in every cell in your body. They are often referred to as our longevity genes due to the health promoting pathways they activate (6).

The multitude of sirtuins means they are found in various cellular compartments including the nucleus, cytoplasm, and mitochondria. SIRT3, 4 and 5 found in the mitochondria and when active help protect mitochondria from damage and ensure the mitochondria are working efficiently. The problem is that sirtuins require NAD+ to be active, so when NAD+ levels decline with age sirtuin activation declines as well (7).

Sirtuins exert their beneficial effects by altering gene expression. Changing which proteins are expressed based on the needs and requirements of the cell, at that time. Within the context of the mitochondria sirtuins support expression of proteins required for energy production, activate antioxidant pathways, and regulate pathways that stimulate mitochondrial biogenesis (production of new mitochondria) (8).

Sirtuins also facilitate communication between the mitochondria and the nucleus to ensure energy production is meeting the demand. As we age and sirtuin activation declines this communication between the mitochondria and the nucleus becomes impaired, so even if the cell is signalling that energy production needs to increase the mitochondria may not alter production (9).

During ATP production, particularly during the electron transport chain highly reactive forms of oxygen are created. They are termed reactive oxygen species (ROS) and they are a natural by-product of energy production, but they can be damaging to mitochondrial DNA as well as other important proteins and structures. Accumulating levels of ROS are known to contribute to the aging process in our cells. To mitigate this the mitochondria has built in antioxidant pathways which are activated by SIRT3 to mop up these ROS and prevent them causing damage to the cell (10).

Overall, sirtuins are vital to maintain cellular health but they are particularly important in maintaining the health and efficiency of our mitochondria. Our mitochondria lie at the heart of energy production so as they decline in numbers and function with age our energy levels plumet. 

Conclusions

Cellular energy production is a large and complex process with many pathways and proteins involved. It is evident that NAD is an essential part of this network with its role as an electron carrier. Furthermore, its role as a signalling molecule and stimulating sirtuin activation is also vital to energy production and mitochondrial health. Therefore, it is no surprise that the age-related decline in NAD+ has impacts on sirtuin activation and mitochondrial function. Although these changes are only a small part of the vast array of pathways involved in cellular aging, they have a large impact on our cellular energy production and subsequently how energised we feel as we get older. That is why NAD+ has become the focus of great scientific research, with many looking at ways to boost cellular NAD+ levels as a tool for healthy aging.

References

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