The science behind NAD+ restoration

NAD+ is a central regulator in critical biological processes, and its decline is linked with the development of aging and age-related diseases. Studies continue to highlight the multitude of benefits that result from increasing NAD+ levels with NAD+ supplements, which are detailed below.

NAD+ is critical for cellular health

NAD+ is a coenzyme and its presence is required to power over 500 biochemical reactions, including:

  • Energy production
  • DNA repair
  • Activation of sirtuins
  • Regulating the circadian rhythm
  • Supporting immune function
  • Epigenetic regulation
  • Maintaining healthy mitochondria
  • Stimulating autophagy and mitophagy

NAD+ levels decline by 50% every 20 years

As we age, NAD+ levels decline by around 50% every 20 years. The decline in cellular NAD+ levels is linked to symptoms of aging such as reduced mental and physical energy, reduced strength and endurance, increased recovery times and the development of age-related diseases such as cognitive decline, metabolic diseases, sarcopenia and frailty.  

Benefits of NAD+ Restoration 

NAD+ restoration is being investigated to slow cellular aging, due to its ability to positively impact the Hallmarks of Aging.

At a cellular level NAD+ restoration has been shown to enhance mitochondrial function (by increasing mitophagy and mitochondrial biogenesis), increase energy metabolism, activate sirtuins (longevity genes), and increase DNA damage repair.

At a whole-body level NAD+ restoration has been demonstrated to restore age-associated muscle loss, increase endurance and strength, increase neurogenesis, improve cognitive function, improve markers of metabolic health, and enhance immune function all of which positively impact healthspan.  


benefits of NAD+ restoration

Figure from ‘NAD+ metabolism and its roles in cellular processes during ageing'. 

Further evidence surrounding the benefits and potential therapeutic applications of NAD+ restoration continue to emerge. NAD+ boosting therapies are currently being investigated as potential treatments for neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, skin conditions such as psoriasis, metabolic diseases such as diabetes, cardiovascular disorders, sarcopenia, chronic fatigue and long covid.  


Why does NAD+ decline?

NAD+ levels decline due to an imbalance between NAD+ production and consumption.

NAD+ decline

The three main pathways which convert NAD+ precursors into NAD+ within the cell are:

  • The Preiss-Handler pathway – which converts the amino acid tryptophan into NAD+. 
  • The de novo pathway - which converts nicotinamide riboside (NR) to nicotinamide mononucleotide (NMN) both of which are NAD+ precursors, used to produce NAD+.
  • The salvage pathway – which recycles nicotinamide (NAM) (another NAD+ precursor) back into NAD+.

  Youthful NAD+ production

The salvage pathway is the largest source of cellular NAD+. This is because when NAD+ is used for reactions within the cell, it is broken down leaving behind the waste product nicotinamide (NAM). The salvage pathway recycles this NAM back into fresh NAD+. The efficiency of the Salvage Pathway in youthful cells ensures optimal NAD+ is produced to supply the reactions which depend on NAD+.

NAD+ production declines, because the rate-limiting enzyme (NAMPT) which powers the salvage pathway declines, causing a loss of NAD+ recycling ability. Simultaneously, NAD+ consumption increases. Two of the major NAD+ consumers are PARPs and CD38. Studies show PARP activation increases with age as DNA damage accumulates, and CD38 activation also increases due to elevated levels of chronic inflammation.

The increased NAD+ consumption in turn generates more waste NAM, and as older cells have decreased ability to recycle this NAM back into fresh NAD+ it accumulates within the cell. To combat this the pathway which removes NAM from the cell is activated, which involves methylation of NAM and can contribute to methyl donor depletion.

Overall, this creates an environment in which key cellular functions are lacking adequate NAD+ and struggle to function optimally. Ultimately, leading to an accumulation of cellular damage that drives the cellular aging process.

Causes of NAD+ decline    
While NAD+ decline is correlated with aging, the rate of NAD+ depletion can be influenced by lifestyle factors and other interventions. Therefore, the majority of the population can implement changes to boost NAD+, reducing their rate of cellular aging and can enjoy the benefits of increased NAD+ levels.