Are NMN and NR Effective Supplements for Depression?

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Can NMN help with depression?
To understand if NMN and NR may be effective supplements for depression, you need to understand the cause and effect of a biochemical chain of events. The four principal actors in this chain are:
  1. Depression, a persistent mood disorder with physiological effects
  2. Sirtuins, a regulator of various biological mechanisms, including some physiological effects of depression
  3. NAD+ (nicotinamide adenine dinucleotide), a coenzyme found in all living cells that's necessary for life
  4. NMN (nicotinamide mononucleotide) and NR (nicotinamide riboside), two precursors (boosters) of NAD+

After taking a look at deleterious effects of depression, I'll explain the interplay between it, sirtuins, NAD+ and finally the last link in this chain, NMN/NR.

Depression, A Worldwide Scourge

Depression - also called major depressive disorder or clinical depression - is a mood disorder that causes a persistent feeling of sadness and loss of interest, says the Mayo Clinic. It affects how you feel, think and behave and can lead to a variety of emotional and physical problems. When depressed, you may have trouble doing normal day-to-day activities, and sometimes there's this persistent feeling that life isn't worth living.

The WHO (World Health Organization) estimates that more than 300 million people worldwide suffer from depression, the world's leading cause of disability and a major contributor to the overall global burden of disease.

Depression is associated with diverse phenomena in the brain such as neuroinflammation, synaptic dysfunction, and cognitive deficit. Studies reported that depression occurs by various metabolic changes, leading to metabolic syndrome. [1]

People take an assortment of supplements for depression, such as St. John's wort, SAMe, 5-HTP, vitamin D - even fish oil, but these may not touch some root biological causes of depression, such as sirtuins. Sirtuins are the next link in the chain.

Sirtuins, A Therapy for Depression

A scientific review published in 2016 summarized recent discoveries regarding the potential relationship between sirtuins and depression, and conclude that sirtuins are promising therapeutic targets to alleviate depression pathology; meaning, it typically expresses, or its behavior.

Nicknamed "the longevity genes", sirtuins are a family of seven proteins (in mammals) that play a multi-faceted role in aging by controlling cellular health and regulating diverse biological mechanisms such as longevity, genomic stability, and inflammation. These are not the dietary proteins we're most familiar with - those found in beans and meats, for instance. In this case we're talking about molecules called proteins, which work throughout the body's cells in a number of different functions. [2]

There's evidence of four possible mechanisms of sirtuin involvement in depression, suggesting that manipulation of sirtuins may be a therapeutic strategy for depression: [3]

  • Sirtuins may control the inflammatory response in depression
  • Sirtuins might regulate the insufficient level of neurotransmitters in depression
  • Sirtuins may improve the synaptic dysfunction caused by depression
  • Sirtuis may alleviate the cognitive decline caused by depression

Sounds good so far, but how do we "manipulate" sirtuins in order to potentially have them alleviate depression, and how do we keep them active?

Answer: Boost NAD+, the focus of the next link in the chain.

NAD+, The Coenzyme of Life

NAD+ is not a supplement for depression, but as you'll soon see, sirtuins need it to properly function. NAD stands for "nicotinamide adenine dinucleotide", a coenzyme found in all living cells and essential for life. NAD+ is the oxidized form of NAD.

The basic problem with NAD+ is that it declines quickly as we age: by age 50 a typical person may have only half the NAD+ they did in youth, and at age 80, NAD+ levels drop to only 1 to 10% of the level expressed in youth. [4]

One major reason that NAD+ is essential for life is that sirtuins need it in order to properly function. In 2016, two of the giants in NAD/sirtuin research, Shin-ichrio Imai, PhD, and Leonard Guarente, PhD, published research delineating the connection between NAD+ and sirtuins.

Here's what they concluded:

  • A tight functional connection between NAD+ and sirtuins has a critical role in regulating physiological robustness, and contributing to aging/longevity control in diverse organisms, from yeast to humans.
  • But NAD+ availability declines as we age, reducing sirtuin activities and affecting the communication between the nucleus and mitochondria at a cellular level and also the inter-tissue communication, particularly between the hypothalamus and adipose tissue, at a systemic level. These events likely cause age-associated pathophysiologies and contribute to the pathogenesis of diseases of aging.
  • For this reason, supplementing key NAD+ intermediates (booster, or precursors), such as NMN (nicotinamide mononucleotide) and NR (nicotinamide riboside), is expected to mitigate age-associated functional decline and ameliorate a variety of age-associated pathophysiologies. The connection between NAD+ and sirtuins will provide deep mechanistic insight into how energy metabolism shapes the process of aging and determines lifespan in evolutionarily diverse organisms.

So, NAD+ needs an intermediary to boost its production and keep it at healthy levels. The supplement that acts as this "intermediary" is what may be helpful for depression; namely, NMN, as well as a similar NAD+ activator, NR - these supplements for depression are the last link in the chain.

NMN and NR, Two Molecules That Boost NAD+ and May Be Effective Supplements for Depression

So far we have looked at: (1) How depression is a worldwide problem, perhaps affecting 300 million people; (2) That sirtuins are a family of proteins that help regulate biological mechanisms, including those that affect the inflammatory response, neurotransmitters, synaptic dysfunction and cognitive decline that are caused by depression; and (3) That sirtuins are dependent on the availability of NAD+. We also touched on how NAD+ levels need to be supported by the precursors NMN or NR, or both. Let's dive into this a bit more.

NMN and NR are often referred to as NAD+ intermediaries because they work to increase the level of NAD+ in our body. A good explanation about NMN's role in boosting NAD+ can be found in a 2018 study published in Cell Metabolism.

The study made this observation:

NMN administration effectively enhances NAD+ biosynthesis in various tissues, including pancreas, liver, adipose tissue, heart, skeletal muscle, kidney, testes, eyes, and blood vessels. NR is protective from weight gain, improves insulin sensitivity, and increases mitochondrial content in skeletal muscle and brown adipose tissue. (Mitochondria are the "energy factory" organelles inside of cells.)

The study's conclusion:

"... two intermediates of NAD+ biosynthesis, nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), effectively increase NAD+ concentration in a variety of tissues, in many cases with beneficial or therapeutic effects."

Among those "therapeutic effects" mentioned is ameliorating the effects of depression. This can happen when NMN and/or NR supplementation boosts NAD+ levels, which then supports sirtuin functionality, making this, as detailed above, a therapeutic strategy for depression.



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