Li Xiang's team at the Institute of Brain Cognition and Brain Disease, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences (Yang Liang was the first author of the paper) published a research paper in Nature Communications entitled: Nicotine rebalances NAD+ homeostasis and improves aging- related symptoms in male mice by enhancing NAMPT activity.
The study found that chronic low-dose nicotine acts as an activator of NAD+ biogenesis and significantly improves NAMPT activity and increases NAD+ synthesis by activating nicotinamide-phosphate ribosyltransferase (NAMPT), a key rate-limiting enzyme in the NAD+ remediation pathway, thereby improving glucose metabolism and cognitive function, as well as aging- related symptoms in male mice. These findings expand the applications of nicotine and provide new targets and approaches for anti-aging.
NAD+ is involved in a number of important biological processes, including cell proliferation and differentiation, energy metabolism, DNA damage repair, epigenetic modification, cellular senescence, inflammation, circadian rhythms, and other important physiological activities. NAD+ levels in the body are progressively depleted with age, and NAD+ depletion is an important hallmark of aging and aging-related diseases.
Interestingly, Nicotine, an important harmful substance in tobacco, is also a secondary metabolite of NAD+ biosynthesis, and the NAD+ pathway is also coordinately regulated by nicotine biosynthesis. Moreover, Nicotine has been found to possess anti-inflammatory and neuroprotective properties. In addition, the NAD+ remediation pathway is conserved across species including bacteria, plants, yeast and mammals. Therefore, the research team speculated that nicotine may play a role in the NAD+ remediation pathway.
With age, the activity of NAMPT, the rate-limiting enzyme of the NAD+ remediation pathway, declines, and its activity is dependent on the extent of its deacetylation by SIRT1. The binding of SIRT1 to NAMPT also decreases with age, resulting in a gradual increase in the level of acetylation of NAMPT.
Higher levels of nicotine are ingested through smoking, which can lead to addiction and long-term harm. In this study, the research team added very low levels of nicotine to drinking water and allowed mice to ingest low doses of nicotine through drinking water.
The results showed that long-term low-dose nicotine intake through drinking water significantly improved NAMPT activity and NAD+ synthesis, which led to improvements in glucose metabolism and cognitive function, as well as symptoms of aging in male mice.
Specifically, low-dose nicotine was able to promote the interaction of SIRT1 with NAMPT and reduce the level of NAMPT acetylation, thereby enhancing NAMPT activity, improving energy metabolism in senescent tissues, and increasing NMN and NAD+ content. PET imaging using F18-FDG small animals as well as hippocampal energetometry assays revealed that nicotine reversed glucose hypermetabolism in senescent male mice.
Specifically, low-dose nicotine was able to promote the interaction of SIRT1 with NAMPT and reduce the level of NAMPT acetylation, thereby enhancing NAMPT activity, improving energy metabolism in senescent tissues, and increasing NMN and NAD+ content. PET imaging using F18-FDG small animals as well as hippocampal energetometry assays revealed that nicotine reversed glucose hypermetabolism in senescent male mice.
In addition, the study found that nicotine stimulates neurogenesis, inhibits neuroinflammation, protects organs from oxidative stress and telomere shortening, ameliorates impaired cellular energy metabolism, and delays age-related degeneration and cognitive decline. And this process does not rely on what used to be thought of as the nicotinic acetylcholine receptor (nAChR).
The study found that chronic low-dose nicotine acts as an activator of NAD+ biogenesis and significantly improves NAMPT activity and increases NAD+ synthesis by activating nicotinamide-phosphate ribosyltransferase (NAMPT), a key rate-limiting enzyme in the NAD+ remediation pathway, thereby improving glucose metabolism and cognitive function, as well as aging- related symptoms in male mice. These findings expand the applications of nicotine and provide new targets and approaches for anti-aging.
NAD+ is involved in a number of important biological processes, including cell proliferation and differentiation, energy metabolism, DNA damage repair, epigenetic modification, cellular senescence, inflammation, circadian rhythms, and other important physiological activities. NAD+ levels in the body are progressively depleted with age, and NAD+ depletion is an important hallmark of aging and aging-related diseases.
Interestingly, Nicotine, an important harmful substance in tobacco, is also a secondary metabolite of NAD+ biosynthesis, and the NAD+ pathway is also coordinately regulated by nicotine biosynthesis. Moreover, Nicotine has been found to possess anti-inflammatory and neuroprotective properties. In addition, the NAD+ remediation pathway is conserved across species including bacteria, plants, yeast and mammals. Therefore, the research team speculated that nicotine may play a role in the NAD+ remediation pathway.
With age, the activity of NAMPT, the rate-limiting enzyme of the NAD+ remediation pathway, declines, and its activity is dependent on the extent of its deacetylation by SIRT1. The binding of SIRT1 to NAMPT also decreases with age, resulting in a gradual increase in the level of acetylation of NAMPT.
Higher levels of nicotine are ingested through smoking, which can lead to addiction and long-term harm. In this study, the research team added very low levels of nicotine to drinking water and allowed mice to ingest low doses of nicotine through drinking water.
The results showed that long-term low-dose nicotine intake through drinking water significantly improved NAMPT activity and NAD+ synthesis, which led to improvements in glucose metabolism and cognitive function, as well as symptoms of aging in male mice.
Specifically, low-dose nicotine was able to promote the interaction of SIRT1 with NAMPT and reduce the level of NAMPT acetylation, thereby enhancing NAMPT activity, improving energy metabolism in senescent tissues, and increasing NMN and NAD+ content. PET imaging using F18-FDG small animals as well as hippocampal energetometry assays revealed that nicotine reversed glucose hypermetabolism in senescent male mice.
Specifically, low-dose nicotine was able to promote the interaction of SIRT1 with NAMPT and reduce the level of NAMPT acetylation, thereby enhancing NAMPT activity, improving energy metabolism in senescent tissues, and increasing NMN and NAD+ content. PET imaging using F18-FDG small animals as well as hippocampal energetometry assays revealed that nicotine reversed glucose hypermetabolism in senescent male mice.
In addition, the study found that nicotine stimulates neurogenesis, inhibits neuroinflammation, protects organs from oxidative stress and telomere shortening, ameliorates impaired cellular energy metabolism, and delays age-related degeneration and cognitive decline. And this process does not rely on what used to be thought of as the nicotinic acetylcholine receptor (nAChR).
Collectively, these findings provide evidence that low-dose nicotine ameliorates age-related symptoms and slows aging by activating the NAD+ remedial pathway.
