Benefits of NR & NMN on Aging and Overall Health
Healthful Vitality | 05/30/2021 | By Dr. Gunjan Chauhan | Benefits of NR & NMN on Aging and Overall Health
Current research summarizes numerous benefits of NR & NMN on aging and overall health. Mainly, NMN protects against several aging-related health declines. Aging is a natural process where the body’s normal homeostasis and functions are altered, resulting in the deterioration and occurrence of age-related diseases. This process can cause several medical problems such as atherosclerosis (1), cancer (2), and neurogenerative disorders, including Alzheimer’s disease (3), immunosenescence (4), and retinal and corneal injury (5). Therefore, for the past few years, researchers have been trying to understand the underlying genetic and molecular markers involved with aging, leading to the introduction of “hallmarks of aging.”
Indeed, significant factors play an essential role in aging, including cellular senescence, epigenetic alterations, genomic instability, telomere attrition, and loss of proteostasis. Besides intrinsic factors, the role of environmental factors in aging is also crucial. For example, our diet and lifestyle strongly impact aging. A recent study mentioned that molecules linked with longevity in an experimental model also influenced cellular nutrient-sensing pathways (6). We explore the benefits of NR & NMN on aging and overall health by expanding our previous research on the Anti-Aging Effects of NR and NMN.
NAD and its impact on aging
One of the critical components found in eukaryotic cells is nicotinamide adenine dinucleotide (NAD), a vital coenzyme regulating enzymatic reactions. It is actively involved in several biological processes, including aging, cell death, gene expression, cell metabolism, and DNA repair (7). Hence, it plays a crucial part in human health and longevity. In recent times, NAD has gained tremendous attention due to its association with sirtuins. Sirtuins are a group of NAD-dependent proteins, especially deacylases (SIRT1–7) (8). This family regulates various vital functions such as cellular activities, energy metabolism, cell growth, circadian rhythm, and stress resistance. Additionally, maintaining telomeres’ length is believed to improve the body’s immunity against the aging process (8).
NR and NMN
Nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) are two crucial NAD+ metabolites that can enhance NAD levels. Studies have shown that deficiency of NAD results in several pathophysiologies, including obesity, heart diseases, macular degeneration, cerebral ischemia, Alzheimer’s disease (AD), and type 2 diabetes. This decline in NAD levels is particularly observed during aging, where multiple organs begin to encounter cellular damage, which contributes to the initiation of age-related disorders (9). Therefore, it arrives that supplementation of NR and NMN could improve NAD levels and serve as an effective therapy for the management of these disorders, as discussed above.
Anti-aging effects of NR and NMN on health: Current research
Here, we elaborate on the significant anti-aging effects of NR and NMN according to recent studies.
a) Retinal degeneration and corneal injury
A study reported that long-term administration of NMN reduced age-related pathological alterations in the eyes (9). In an animal model, mutation in rd8 of C57BL/6N led to the accumulation of macrophages and subretinal microglia as age progressed. This was similar to an increased level of light-colored spots detected in the fundus of the eyes (10). When assessed at 17 months of age, several of these spots were seen in the fundus of C57BL/6N mice. On the contrary, mice who were administered NMN supplements had significantly less number of spots in the fundus. Long term supplementation of NR and NMN have been shown to improve rod cells function and enhance scotopic b and photopic b waves in animal models. This demonstrates that these supplements can ameliorate retinal degeneration, improve performance of cone cells and prevent corneal injury (9).
b) Neurodegenerative diseases
Neurodegenerative diseases encompasses a range of diseases with mitochondrial dysfunction. Few of such conditions are Alzheimer’s disease (AD), Huntington’s disease and Parkinson’s disease (11). One of the most common condition that demonstrates alteration in mitochondrial structure and functions is AD, leading to impairment in the electron transport chain and energy production (12). Therefore, adequate levels of NAD and its metabolites may boost cellular energy which will help in management of neurodegenerative diseases (12).
Research has shown that abnormalities in mitochondria lead to generation of reactive oxygen species (ROS) and excessive accumulation of free radicals can induce further damage to the mitochondria, causing fragmentation (13). It is observed that treatment with NR and NMN activates SIRT3-dependent deacetylation of SOD2, thereby decreases production of ROS in hippocampus, which results in lowering damage to mitochondria. Furthermore, NMN reduces production of b-amyloid and plaque accumulation in AD (14).
c) Cardiomyopathies
Heart failure is a condition where mitochondrial respiration gets impaired (15). It is found that lack of Ndufs4 (protein required to maintain the heart stable) causes significant damage to heart functions. Studies have shown that supplementation of NR and NMN improves overall performance of heart in a SIRT3-dependent manner, as observed in an animal model (16). NR and NMN improve the diastolic functions, reduce production of lactate, and promote heart contractility. Although, all these improvements were seen in cardiomyopathy model in mouse, but it strongly provides preclinical evidence that NR and NMN could be used as effective drugs in heart failure and cardiomyopathies (16).
d) Vascular dysfunction
Cardiovascular disease (CVD) is a common medical condition affecting population worldwide. Aging is considered to be a risk factor for CVD. There are two main predictors associated with clinical CVD, including vascular endothelial dysfunction and stiffness of large arteries (17). The main reason that bring these changes is vascular oxidative stress (18). Age-related depletion of NAD and associated dysregulation of SIRT1 directly affect angiogenic processes in cerebromicrovascular. Studies have reported that NR and NMN could improve angiogeneic properties in aged endothelial cells (19). Additionally, recently it has been identified that supplementation of NR and NMN could reverse age changes when it comes to gene expression of neurovascular components, including anti-apoptotic, mitochondrial protection and activation of SIRT1 (20).
Recent development
Reproductive aging in females results in loss of oocyte quality, an irreversible process associated with reduced levels of NAD (21). Recent studies report that NMN and NR administration can restore oocyte quality, and improve fertility in aged animal models. It was shown that adverse effect on the developing embryo due to maternal age were reversed by NMN. Hence, it is believed that among women it can help in the maintenance of reproductive functions, irrespective of age (21). Another study demonstrated that treatment with NR and NMN can enhance self-renewal properties in mesenchymal stromal cells which resulted in improved osteogenesis in aged mice (22)
Covid-19 and role of NR and NMN
COVID-19 has affected people of all age groups. However, the mortality rate varies. This issue suggests the role of immunosenescence or epigenetic factors among the different age groups. Indeed, immunosenescence is an age-associated impairment of the body’s defense system that increases infection risk (22). This case makes older adults more susceptible to infections, including COVID-19 (23). There is a higher risk for older adults who generally encounter several complications due to compromised immune systems and altered respiratory functions associated with aging. The hypothesis is that anti-aging immunomodulators such as NAD will be able to boost the immune response and increase their lifespan (23).
Future perspective: NMN and Human Health
In fact, NR and NMN are key components that have shown significant anti-aging effects. However, majority of evidence is based on animal studies. When it comes to human, currently a lot of research is underway. Notably, Imai, a renowned researcher believes that NR and NMN will enhance cellular and molecular metabolism in humans, making them appear 10-20 years younger (24). Imai and his team of researchers are studying NMN in humans.
A Harvard-based researcher who has conducted several famous studies concerning anti-aging, NAD+ and sirtuins, is also conducting human trials. Interestingly, he was using NMN on himself and reported that since NMN supplementation, he is feeling a lot more energetic, his lipid profile has improved, and blood markers have shown levels similar to that of a 30-year-old when his actual age is 60 years. (25) This highlight the profound anti-aging properties of NR and NMN. As science advances, our understanding and knowledge of these components will also broaden.
Conclusion
The decline in NAD+ levels is a critical factor in many age-related pathophysiologies. Notably, measures that could stabilize NAD and improve production of NAD+ are rapidly being explored in aging tissues. Besides, several chemical and genetic approaches have been identified that have slow down aging/senescence in animal models and human trials. Indeed, administration of NR and NMN will prove beneficial and a powerful tool to effectively manage age-related medical conditions. Indeed, further studies that could specifically identify activators of NAD will revolutionize our knowledge associated with aging and its molecular mechanism. Surely, it will help in the development of effective interventions that will promote healthy and productive aging.
References
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