A recent study reported that long-term nicotine consumption had a positive impact on motor function in male mice. The beneficial effects were mediated by sphingolipid and NAD+ metabolism [1].
Two faces of tobacco smoking
Smoking tobacco is widely considered detrimental to health for multiple good reasons, as it has been associated with increased risks of cancer [2], type 2 diabetes [3], and premature mortality. [4]. However, there is also a lesser-known, different face of smoking. Epidemiological studies have reported associations between smoking and positive effects on the risk of certain inflammatory and neurodegenerative diseases [5], such as Parkinson’s disease [6] and type I diabetes [7].
Those positive associations are most likely due to the effects of nicotine and not the other components of tobacco smoke, especially since recent research has linked nicotine to increased NAD+ biosynthesis and improvements in metabolic resilience [8]. These benefits were observed at nicotine concentrations much lower than those experienced while smoking, suggesting the need for investigating dose-dependent nicotine effects.
Youthful motor functions
In this study, the researchers investigated the long-term effects of nicotine by adding nicotine to mice’s drinking water at low or high doses starting when mice were 8 weeks of age and continuing for 22 months.
In aged mice that received nicotine, the researchers observed increased locomotor and general activity, enhanced motor strength and endurance, and reduced anxiety-like behaviors compared to aged controls, especially in mice that received higher nicotine doses. The researchers reported that the behavioral patterns of aged mice that received the highest dose of nicotine were most similar to those of the young mice. Also, postural dynamics, which assess how the body maintains balance and stability, of nicotine-treated aged mice showed patterns more similar to those of young controls.
These observations suggest a protective effect of nicotine on motor functions and anxiety-like behavior. Such a protective effect was not observed for cognitive function since the researchers didn’t observe significant differences between groups in memory performance tests.
Linking metabolism with motor functions
A metabolic analysis followed the behavioral and motor function observations. The researchers observed no significant differences between nicotine-treated and untreated aged mice in glucose tolerance tests, insulin tolerance tests, or body weight. However, there were alterations in the distribution of adipose tissue, with the group that received the highest nicotine dose having an elevated visceral-to-subcutaneous fat ratio.
The researchers analyzed all the metabolites across multiple organs, which revealed changes in metabolism caused by nicotine consumption and suggested that both the low dose and the high dose of nicotine partially reversed age-associated metabolic changes. This analysis revealed that nicotine alters the levels of many energy-related metabolites, including changes in amino acid and NAD+ metabolism, suggesting to the researchers that nicotine modulates energy-related metabolic pathways.
These changes in metabolic pathways were also linked to motor functions in aged mice. An analysis of the high-dose group revealed a correlation between significantly altered metabolites and locomotor behaviors.
The researchers concluded that their “findings suggest that nicotine exerts its effects on motor function in aged mice by reshaping metabolic networks, primarily through glucose and lipid-related pathways,” with white adipose tissue being the central mediator of these nicotine-induced metabolic changes. They believe that increased energy expenditure might be responsible for the improved motor performance of nicotine-treated mice.
Behavior-Metabolome Age Score
To quantify the effects of nicotine on biological aging, the researchers developed a composite score called the Behavior-Metabolome Age Score (BMAge score). It includes results from multiple behavioral assays and metabolic profiles from multiple tissues.
The BMAge score of the aged mice treated with high nicotine doses showed the most similarities to that of the young animals. In contrast, the group that received a lower nicotine dose showed intermediate results. While BMAge is useful in these experiments, since it’s a new tool, it should be validated on different cohorts.
Shifting microbiotal composition
Due to the nicotine delivery method (drinking water), nicotine had direct contact with the intestine, and it could impact gut microbiota. Therefore, the researchers tested whether the nicotine impacted microbes in the gut by sequencing the mice’s fecal samples every 4 weeks, starting at 12 months of age. The results revealed a nicotine-induced shift in microbial communities’ structures and found that nicotine treatment was associated with the upregulation of gut microbes known for supporting gut homeostasis and anti-aging effects.
Profiling of microbiota-derived metabolites also revealed substantial nicotine-associated shifts in metabolic profiles. In particular, there were changes to metabolites of the sphingolipid pathway and a decrease in ceramide, which has been linked to age-associated metabolic disorders [9]. In the plasma of high-dose nicotine-treated mice, they also observed increased sphingomyelin and an elevated sphingomyelin/ceramide ratio, which they suggest could serve as an age-related biomarker.
Nicotine administration also substantially altered the expression of enzymes involved in sphingolipid metabolism as well as increased the levels of nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in NAD+ biosynthesis, which is in line with increased NAD+ levels in muscles. The essential role of these enzymes in nicotine-mediated sphingolipid and NAD+ metabolism remodeling was confirmed using mouse myoblast cell cultures.
Context-dependent findings
All in all, the researchers concluded that nicotine-induced NAD+ availability positively impacts energy metabolism in aged mice and impacts sphingolipid turnover. These metabolic changes were correlated with improved motor performance and molecular profiles similar to those of young mice.
Under the conditions tested, the researchers didn’t observe any organ toxicity or adverse effects resulting from long-term nicotine intake; however, they caution against extrapolating the findings to humans, since there are known risks regarding nicotine, such as its addictive nature. The researchers also investigated nicotine only in male mice and didn’t address any potential sex-dependent differences.
While this study shows a positive impact of nicotine, the researchers discuss that previous literature showed different, sometimes conflicting results regarding the effects of nicotine. They believe that the differences stem from the route of delivery, length of treatment, and the dose, making the biological effects of nicotine treatment context-dependent.
Literature
[1] Jia, S., Jing, X., Wang, R., Su, M., Wang, P., Feng, Y., Ren, X., Tu, L., Wei, P., Lu, Z., Jia, Y., Hong, F., Mo, Z., Zou, J., Huang, K., Yan, C., Zou, Q., Wang, L., Zhong, G., Zeng, Z., … Liu, X. A. (2025). Nicotine Reprograms Aging-Related Metabolism and Protects Against Motor Decline in Mice. Advanced science (Weinheim, Baden-Wurttemberg, Germany), e15311. Advance online publication.
[2] Grando S. A. (2014). Connections of nicotine to cancer. Nature reviews. Cancer, 14(6), 419–429.
[3] Chen, Z., Liu, X. A., & Kenny, P. J. (2023). Central and peripheral actions of nicotine that influence blood glucose homeostasis and the development of diabetes. Pharmacological research, 194, 106860.
[4] GBD 2021 Tobacco Forecasting Collaborators (2024). Forecasting the effects of smoking prevalence scenarios on years of life lost and life expectancy from 2022 to 2050: a systematic analysis for the Global Burden of Disease Study 2021. The Lancet. Public health, 9(10), e729–e744.
[5] Piao, W. H., Campagnolo, D., Dayao, C., Lukas, R. J., Wu, J., & Shi, F. D. (2009). Nicotine and inflammatory neurological disorders. Acta pharmacologica Sinica, 30(6), 715–722.
[6] Ascherio, A., & Schwarzschild, M. A. (2016). The epidemiology of Parkinson’s disease: risk factors and prevention. The Lancet. Neurology, 15(12), 1257–1272.
[7] Wei, Y., Edstorp, J., Feychting, M., Andersson, T., & Carlsson, S. (2023). Prenatal and adult exposure to smoking and incidence of type 1 diabetes in children and adults-a nationwide cohort study with a family-based design. The Lancet regional health. Europe, 36, 100775.
[8] Yang, L., Shen, J., Liu, C., Kuang, Z., Tang, Y., Qian, Z., Guan, M., Yang, Y., Zhan, Y., Li, N., & Li, X. (2023). Nicotine rebalances NAD+ homeostasis and improves aging-related symptoms in male mice by enhancing NAMPT activity. Nature communications, 14(1), 900.
[9] Laurila, P. P., Wohlwend, M., Imamura de Lima, T., Luan, P., Herzig, S., Zanou, N., Crisol, B., Bou-Sleiman, M., Porcu, E., Gallart-Ayala, H., Handzlik, M. K., Wang, Q., Jain, S., D’Amico, D., Salonen, M., Metallo, C. M., Kutalik, Z., Eichmann, T. O., Place, N., Ivanisevic, J., … Auwerx, J. (2022). Sphingolipids accumulate in aged muscle, and their reduction counteracts sarcopenia. Nature aging, 2(12), 1159–1175.
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