AT WHAT AGE DO OUR NAD+ LEVELS START TO DECLINE?

Key Pointers

  • Degradation of NAD+ happens through multiple mechanisms
  • NAD+ levels decrease mostly due to consumption and catabolism
  • NAD+ levels universally decrease with age, but the extent will vary according to system and age group

Exploratory studies have proven that there is a decline in NAD+ with advancing age. Many mechanisms can explain the phenomenon, some being more understood than others. One of the more straightforward mechanisms is the direct decrease of NAD+ biosynthesis due to decreased NAMPT salvaging activity, but this has not been extensively studied in mammalian subjects. Another mechanism is an increased consumption of NAD+ as a co-substrate in enzymatic pathways that are anti-inflammatory with CD38 and CD157 and pertain to DNA damage with PARPs. 


CD38, which is an ADP-ribose synthase, is NAD+ dependent for its activity in mRNA expression, which increases with aging. As more inflammatory processes happen with age due to lifelong stress, NAD+ consumption by CD38 will gradually increase with age, especially in immune cells. Levels of CD38 and NAD+ are inversely proportional as it was observed that a CD38 knockout in rodents resulted in a 50% increase in NAD+ levels. One of the rodent studies found that by the age of 32 months, control mice had half the NAD+ concentration when compared to mice with CD38 knockout. 


Similar to CD38, PARPs’ activity increases with age in response to increased and continuous DNA damage that either results from chronic stress, chronic inflammation, or the senescence itself. This has been correlated with decreased NAD+ levels and proven by studies that investigated the relationship and found that knockout mutation in rodents resulted in higher NAD+ concentrations. 

The extent of the drop is variable between cells, systems, and living models; but it is a universal observation in study animals and humans. In rodents, NAD+ levels were mostly studied in hepatic, muscular, and brain tissues. In humans, NAD+ levels reduction was studied in skin cells, cerebrospinal fluid, brain tissue, and plasma.


A 2012 study of human skin cells found that local NAD+ concentrations dropped by 50% in the process of aging, with a more rapid decline in older adults than in children. Another 2014 study found that individuals aged above 45 had a 10 to 15% decrease of levels in the cerebrospinal fluid compared to those who are 45 or younger. There is some conflicting data when it comes to brain tissue’s NAD+ concentrations, as evidence is not concrete on the difference between younger adults and older ones, but the general observation found a decline with age. When considering hepatic tissue, studies evidenced that individuals above the age of 60 had roughly a 10 to 25% reduction of NAD+ levels, compared to 45 years old ones. A plasma-focused study in 2019 established an age group-related decline in NAD+ levels; subjects who are 60 or older had broadly lower levels than the 30 to 40 years old age group.


Conclusion

NAD+ is a prominent molecule that is constantly synthesized, catabolized, and recycled through the life cycle. To understand its importance, its involvement in different metabolic and functional pathways, and how it is consumed and degraded, should be understood. The effects of its decrease and decline are complexly intertwined with bodily functions and their level of activity through aging.  

References

  1. McReynolds MR, Chellappa K, Baur JA. Age-related NAD+ decline [published online ahead of print, 2020 Feb 22]. Exp Gerontol. 2020;134:110888. doi:10.1016/j.exger.2020.110888 
  2. 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
  3. 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