CAN NAD+ SLOW DOWN THE NEGATIVE AGING CYCLE?

Key Pointers

  • NAD+ is a key regulator in bodily functions
  • NAD+ homeostasis is disrupted with age 
  • NAD+ protects against most age-related disorders 

Aging is a natural and gradual process that starts in adulthood and stops upon death. It is an accumulation of internal processes that result in a decline of bodily functions. The most common age-related physiological changes are cardiovascular diseases, neurodegeneration, muscle weakness, and endurance. NAD+ is an abundant coenzyme present in all cells. It has multiple roles in metabolic pathways and cellular functions and plays a key role in aging.


NAD+ is involved in three major regulatory enzymes’ pathways; Sirtuins, poly-ADP-ribose polymerases (PARPs), and cyclic ADP-ribose synthases, also known as CD38 and CD157. PARPs mostly regulate DNA repair and inflammation, while CD38 and CD157 regulate metabolism and inflammation. Sirtuins have a broader role in longevity, circadian rhythm, metabolism, cardiovascular diseases, and neurodegenerative pathophysiology among many others.


Throughout the life span, NAD+ is in homeostasis and is constantly being synthesized and catabolized. With aging and cellular senescence, NAD+ depletes as it becomes less synthesized. The depletion is hypothesized to be secondary to reduced nicotinamide phosphoribosyltransferase (NAMPT) expression, excessive PARP activation, and lifelong DNA damage and inflammatory processes.


The decrease in NAD+ levels and compromised availability in metabolic and functional pathways has been evidenced to lead to a plethora of age-related pathologies. Since NAD+ levels and aging have an inversely proportional relationship, it makes sense to consider NAD+ supplementation as a means to slow down aging. 


It has been established that Sirt1 has a protective effect on neurodegeneration that results from lifelong nuclear DNA damage that accumulated over time. Some of the age-related neurodegenerative diseases are Alzheimer's, Parkinson's, and Huntington’s disease. Multiple rodent studies where Sirt1 has either been overexpressed or reduced, found that it had positive and negative detrimental impacts on the disease’s progression, respectively.


When NAD+ was tested in mice, results showed an increase in NAD+ that had a protective effect against ischemic brain injury and MPTP-induced parkinsonism. NAD+ administration in another set of rodents with Alzheimer’s disease was investigated, and it was found that supplementing this NAD+ precursor had a positive effect on cognitive and behavioral activity.


Since NAD+ is highly involved in ATP production and mitochondrial activity, it can affect muscle strength and endurance. This is especially observed in older models as they become increasingly weaker when NAMPT in muscles and overall NAD+ levels decrease.


The administration of NAD+ can strengthen weakened muscles by bypassing NAMPT, enhancing muscle stems cells, increasing mitochondrial function, and improving muscular dystrophy. A rodent study that particularly focused on the effect of NAD+ depletion and supplementation in older models’ skeletal muscles, found that controlling NAD+ levels helped with endurance.


Cardiovascular pathology is the most associated with aging and is one to impact the quality of life in the geriatric population. NAD+ has repeatedly been proven to be a significant factor in their physiology and progression. Sirt3 is vital for regular heart function and protects it from injury.


Sirt3 knockout was studied in rodents, and results found premature cardiac hypertrophy and fibrosis, which was either slowed down or reversed when treated with NAD+. Another benefit of NAD+ is an amelioration in blood flow through the Sirt1-dependent promotion of endothelial cells and vascular density.


Conclusion

In an ever-growing elderly population, the focus on improving geriatric quality of health is crucial. NAD+ is a promising molecule when it comes to combating aging and slowing down its pathophysiological ailments by controlling senescence. 

References

  1. Rajman L, Chwalek K, Sinclair DA. Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence. Cell Metab. 2018;27(3):529-547. doi:10.1016/j.cmet.2018.02.011
  2. Sultani G, Samsudeen AF, Osborne B, Turner N. NAD+: A key metabolic regulator with great therapeutic potential. J Neuroendocrinol. 2017;29(10):10.1111/jne.12508. doi:10.1111/jne.12508
  3. Imai S, Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 2014;24(8):464-471. doi:10.1016/j.tcb.2014.04.002