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NAD+ Depletion: The Impact of a Sedentary Lifestyle

Caitlin Beale, MS, RDN

It's well understood that a sedentary lifestyle isn't great for our long-term health, especially when it comes to the aging process. Regular physical activity has many benefits, from reducing the risk of chronic diseases to improving mental health and cognitive function. One reason physical activity is so important may be related to increased NAD+ (nicotinamide adenine dinucleotide) levels. This post will outline the relationship between NAD+ depletion and physical activity.

What Is NAD+?

NAD+ is a coenzyme vital to the many biological processes carried out by every living cell. It plays an essential role in over 500 enzymatic reactions including cellular energy production and cell repair. 

As a coenzyme, NAD+ facilitates the function of the enzymes that build energy in the mitochondria, which is also known as the powerhouse of the cell. By powering these enzymes, NAD+ helps generate 90% of the body’s energy

Unfortunately, research shows that NAD+ levels decline up to 65% between the ages of 30 and 70 (based on Massudi et al., 2012; Janssens et al., 2022). This depletion is connected to a decrease in cellular energy and repair, which can potentially lead to accelerated aging.

NAD Declines graph

What Is NAD+ Depletion? 

Going deeper into the science, NAD+ depletion can cause mitochondrial dysfunction, which leads not only to a decline in energy production, but an accumulation of ROS (reactive oxygen species). ROS are unstable molecules containing oxygen that easily react with other molecules in a cell, resulting in oxidative stress. Oxidative stress is the imbalance between free radicals and antioxidants. Free radicals are caused by environmental factors as well as the body's own energy production process.

The increase in ROS and oxidative stress leads to chronic PARP activation. PARP is a type of enzyme that helps stressed and damaged cells repair themselves. While PARP does a great job repairing cells, it rapidly consumes available NAD+, which leads to a decrease in NAD-dependent sirtuin activity. Sirtuins need NAD+ to help keep chromosomes stable, repair damaged DNA, and reduce cellular stress. 

Without the proper NAD+ supply, cellular aging can happen much more rapidly. And a buildup of ROS in cells may cause damage to DNA, RNA, and proteins, and even cell death. 

There are many factors that lead up to NAD+ depletion as a person ages, but a sedentary lifestyle can speed up this process. 

2024-02 SA Fang et al Redesign Zoomed In Gif

The Relationship Between Physical Activity and NAD+ Levels 

As reported in Physiology Reports, one strategy for reversing age-related NAD+ decline is regular exercise.  

In the process of extracting energy, muscle contraction activates enzymes that generate NAD+, which in turn helps muscle cells generate the energy they need to contract. This is a positively reinforcing circular process, with NAD+ being an indicator of energy demand. As muscle contraction requires more fuel, it generates more NAD+, letting the body know to speed up metabolism and in turn provide more fuel for the muscle. 

In a study published in Nature Aging, researchers examined 52 people divided between young and older adults. Older adults were separated into three groups: trained, normal, and impaired. NAD+ was significantly lower in older participants, and those who were the least active had the lowest levels of NAD+. Young adults tended to have higher NAD+ levels than older adults. Interestingly, younger participants in the study had similar NAD+ levels as the most active older participants.

Mitochondrial health and muscle function were positively associated with higher NAD+ levels. NAD+ levels were also higher for those with more average steps per day. In other words, the more someone moved each day, the higher the NAD+ levels.

How Does a Sedentary Lifestyle Deplete NAD+?

The impact of a sedentary lifestyle on NAD+ isn't fully understood, and it's likely complex. Research hypothesizes that it may be partly due to a rate-limiting step in the pathway that generates NAD+ in your muscle cells.

The enzyme nicotinamide phosphoribosyltransferase (NAMPT) helps to create NAD+. NAMPT is found in mitochondria, and according to a study from the American Journal of Physiology, Endocrinology and Metabolism, levels of NAMPT are lower in people who are sedentary.

NAMPT also decreases with age, but physical activity can increase it, according to a study published in Physiological Reports. In this study, both young and older adults who participated in 12 weeks of aerobic and resistance exercise increased their NAMPT levels—with older adults seeing more significant improvements. 

A Sedentary Lifestyle Accelerates the Aging Process

A sedentary lifestyle contributes to weaker bones and sarcopenia. Sarcopenia is the loss of muscle mass and strength that can occur with aging. Some muscle loss is considered a normal part of the aging process, but it can be accelerated by lack of exercise and poor nutrition. 

The result is a decreased quality of life, frailty, lack of mobility, and an increased risk of falls and fractures, which only advances the aging process. But it doesn't have to be this way. Exercise is considered one of the most effective ways to prevent or reverse sarcopenia. 

According to an animal study published in Cell Death and Disease, mitochondrial dysfunction is also linked to sarcopenia. A study in Nature Communications took muscle biopsies from older adult men and found that those with sarcopenia had lower mitochondrial activity and low NAD+ levels. 

So staying active to support muscle mass and mitochondrial health, thereby increasing NAD+ levels—could be one way to maintain healthy mobility and keep sarcopenia at bay.

Supplementing with an NAD+ Precursor Can Add Another Layer of Support

Healthy aging takes a multifaceted approach that goes beyond physical activity. Diet, sleep, stress management, and other environmental and lifestyle factors all play a role. And while we can't turn back the hands of time, supplementing with NAD+ precursors can be an additional tool to support cellular health.

NAD+ precursors are molecules that the body can convert into NAD+. Studies show that supplementing with precursors helps your body generate more NAD+. A study published in Scientific Reports concluded that supplementation with nicotinamide riboside (NR) effectively increases NAD+ levels in the body.

A mouse study published in Cell Metabolism also found that supplementing with NR helped support muscle strength and endurance. In humans, NR supplementation can decrease oxidative stress and may enhance physical performance in older adults, according to a study from the European Journal of Nutrition.

NAD+ precursors are also linked to positive changes in other aspects of healthy aging, including brain health, cardiovascular conditioning, insulin sensitivity, and other markers of metabolic health, according to a review in Cell Metabolism.

There's no doubt that a sedentary lifestyle is a risk factor for aging, but there are ways to offset that damage—not to mention increasing physical activity, if possible. Increasing NAD+ levels with supplements like NR may help protect against some of the adverse effects of a sedentary lifestyle and support healthy aging.

Key Takeaways: Physical Activity Is a Vital Component of Healthy Aging

A sedentary lifestyle lowers NAD+ levels, alters mitochondrial health, and contributes to aging, but you can counteract these effects by regularly moving your body.

How a Sedentary Lifestyle Affects Your Cells - Solution Image

NAD+ precursors may also help and have been linked to positive changes in other aspects of healthy aging and other markers of metabolic health. 

In combination with increased physical activity and other healthy lifestyle habits, supplementation with NAD+ precursors like Tru Niagen can offer a simple yet effective way to fight back against the effects of aging and improve the quality of life as we grow older.

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