NAD+ Aging Research in Mice
For people researching the potential role of NAD+ supplementation as part of an approach to maintain physical and cognitive performance as we age or to delay the biological process altogether, the scientific data generated from mouse models can provide useful insight.
It is well established amongst the scientific research community that NAD+ has crucial roles in many cellular processes and, as a result, pathways that boost NAD+ are attractive targets for drug discovery. As part of the well-defined drug discovery process, animal models enable early testing for safety and efficacy before compounds are introduced to humans. In fact, organizations such as the US FDA rely on data generated from animals to assess the safety and efficacy of new drugs.
Mouse models are the most used animal model in the drug discovery process. When combined with recent advances in genome sequencing these mouse models become very robust and powerful techniques in testing specific hypotheses or treatment effects.
Aging and Longevity Research in Mice
Boosting NAD+ levels has been found to have a profound effect on the health and survival of mammals. In fact, multiple scientific studies have now shown that if you prevent NAD+ levels from declining in your cells as you age, or indeed restore them to youthful levels, you can prevent the negative impact of low NAD+ levels on aging.
The decline in cellular NAD+ levels with progressive age is found to occur across all species from yeast to humans and is considered one of the major contributing factors to the reason organisms age and develop age-related diseases. With this in mind, there is great interest amongst the scientific community of using NAD+ boosting therapeutics as a way to delay aging and age-related physical decline.
Liver Function
NAD+ has been found to play a key role in liver function and protection. In mice, NAD+ levels are found to decrease 2-fold by mid-age. This causes a range of problems including the development of fatty liver disease, fibrosis and insulin resistance. Raising NAD+ back to the levels found in a young mouse, has been found to be effective at not only improving the health of the liver, but also increasing its capacity for regeneration and offering protection against hepatotoxicity.
Kidney Function
A large body of evidence now points towards reduced levels of NAD+ leading to reduced kidney function and resilience with age. In support of this theory, boosting NAD+ levels in mice has been found to offer renoprotection against acute kidney injury.
Skeletal Muscle Function
Sarcopenia, the loss of skeletal muscle mass and strength, is a major concern of aging. As we age our muscles become weaker, they are less sensitive to insulin, they have less mitochondria to produce energy and more inflammation. Boosting NAD+ levels in old mice using NAD+ precursors dramatically improved muscle function and endurance. At a cellular level it was found to increase both mitochondrial function and ATP production. Higher NAD+ in muscles has also been shown to increase the number and quality of muscle stem cells, which in turn enhances muscle regeneration and recovery in old mice.
Diabetes
As well as a poor diet, your age increases your risk of developing type 2 diabetes. In diabetic mice, NAD levels are found to be markedly reduced. Scientists were able to reverse this diabetes using interventions to increase NAD+ levels. This resulted in restoration of normal blood glucose in the mice and also reversed other signs of diabetes such as insulin resistance.
Cardiac Function
High NAD levels have been found to be important in both normal heart function and also recovery from injury. Boosting NAD+ has been found to improve heart function in old mice and restore cardiac function in mouse models of heart failure. Heart muscle is very metabolically active, and the benefits of NAD+ seem to arise from its ability to improve mitochondrial efficiency, leading to better ATP production to support the high energy demand.
Vascular Function
Vascular diseases effect the blood vessels and their failure over time is one of biggest factors contributing to the decline in quality of life after age 65. Fully functioning arteries, veins and capillaries are vital to makes sure that all areas of the body receive oxygen, nutrients and have waste removed. Increasing NAD+ levels in mice has been shown to increase blood flow and capillary density in elderly mice.
Inflammation
As we age the level of inflammation in our body generally increases and we suffer from chronic low grade inflammation which is known to lead to various other age-related pathologies. Boosting NAD levels has been found to have anti-inflammatory effects in both mice and humans, reducing circulating inflammatory factors and also muscle inflammation.
Immunity
Immune cells upregulate the NAD+ salvage pathway to maintain NAD+ levels during activation. Accordingly, NAD depletion has been shown to impair T-cell differentiation and proliferation.
Increasing NAD+ generation during an immune challenge in aged immune cells was found to restore immune responses. A reduction in NAD+ synthesis in immune cells may underlie the decreased innate immune function that occurs with age.
Vision
Research shows that NAD depletion may play a key role in retinal degeneration that occurs with age leading to loss of vision. Mouse models of retinal dysfunction exhibit early retinal NAD+ deficiency and studies have found that limiting natural NAD+ synthesis in the photoreceptors in mice results in loss of vision. Importantly, boosting NAD levels in mice with age-related macular degeneration was found to reverses the damage and restore vision.
Hearing
Reduction of NAD during ageing is an important contributor to hearing loss. In mouse models of age related hearing loss, supplementing NAD+ levels was found to prevent hearing loss. Boosting NAD levels has also been shown to protect nerve cells in the inner ear from damage induced by loud noise.
Neuronal Function
It is widely known that neuronal function declines with age and unsurprisingly NAD levels are key to neuronal function and survival. NAD has been found to protect damaged neurons and helps to delay the effects of several neurodegenerative diseases in mouse models of Alzheimer’s disease, Parkinson’s disease and ALS. In Alzheimer’s disease, treatments to boost NAD levels improved cognition in mice and NAD was found to protect nerves after damage and allow them to regenerate.
NAD boosting regimes have also been shown to prevent and in some cases reverse neuronal degeneration associated with hearing loss, traumatic brain injury and retinal damage.
Fertility
There is an ongoing trend across the developed world to defer pregnancy until later in life, but this has become a significant challenge to family planning, because of the irreversible decline in female fertility with age. A loss in female fertility is associated with oocyte dysfunction and falling NAD levels have been found to play a role within this process. In support of this, strategies to boost NAD levels in aged mice were able to improve oocyte quality and restore fertility.
Ultimately, the scientific data generated from animal models as part of extensive drug discovery processes shows consistently that maintaining your NAD+ levels slows your rate of aging and increases your healthspan; the number of years you will live in good health, independent and free from frailty or disease. Importantly, the drug discovery programs have also identified specific compounds which have been shown to positively influence the different pathways involved in boosting levels of NAD+.
References
Minhas, P.S., Liu, L., Moon, P.K., Joshi, A.U., Dove, C., Mhatre, S., Contrepois, K., Wang, Q., Lee, B.A., Coronado, M. and Bernstein, D., (2019). Macrophage de novo NAD+ synthesis specifies immune function in aging and inflammation. Nature immunology, 20(1): 50-63.
Tullius, S.G., Biefer, H.R.C., Li, S., Trachtenberg, A.J., Edtinger, K., Quante, M., Krenzien, F., Uehara, H., Yang, X., Kissick, H.T. and Kuo, W.P., (2014). NAD+ protects against EAE by regulating CD4+ T-cell differentiation. Nature communications, 5(1): 1-17.
Bruzzone, S., Fruscione, F., Morando, S., Ferrando, T., Poggi, A., Garuti, A., D'Urso, A., Selmo, M., Benvenuto, F., Cea, M. and Zoppoli, G., (2009). Catastrophic NAD+ depletion in activated T lymphocytes through Nampt inhibition reduces demyelination and disability in EAE. PloS one, 4(11): 7897.