Evidence shows that life-long oral nicotine shapes motor and metabolic aging in mice

Aging is a systemic process marked by energy imbalance and organ-specific metabolic decline, with motor deterioration emerging as a key component of frailty. As the global population aging, challenges remain in healthy aging.

Nicotine is the principal bioactive compound in tobacco. Smoking accelerates metabolic and cardiovascular disease. However, epidemiological studies suggest that smokers have lower risks of certain neurodegenerative disorders such as Parkinson's disease. It is unclear that whether nicotine itself can influence aging trajectories.

In a study published in Advanced Science, a team led by Prof. LIU Xin'an and Prof. CHEN Zuxin at the Shenzhen Institutes of Advanced Technology of the Chinese Academy of Sciences, along with collaborators, for the first time demonstrated that life-long oral nicotine administration reprograms aging-related systemic metabolism via the sphingolipid-energy metabolic axis, and attenuates age-associated motor decline in mice.

A 22‑month longitudinal experiment was conducted to examine the effects of life‑long oral nicotine exposure in mice. Moderate or high doses of highly purified nicotine were added to drinking water to mimic plasma concentrations in human smokers but without combustion byproducts. Nicotine's systemic effects on aging were mapped through high‑precision three-dimensional (3D) behavioral tracking, multi‑organ metabolomics, gut microbiota sequencing, and cell‑based assays.

Researchers discovered that nicotine reprograms aging‑associated metabolism in a dose‑dependent manner, particularly through glycolipid and sphingolipid pathways. These changes enhanced nicotinamide adenine dinucleotide availability, limited ceramide accumulation, and improved energy homeostasis, which are molecular adaptations that correlated with delayed motor decline.

Longitudinal gut microbiota analysis revealed preserved microbial diversity and the enrichment of sphingolipid‑related metabolites linked to sarcopenia prevention. By integrating behavioral and metabolic profiles, researchers developed a "Behavior‑Metabolome Age" score, and confirmed that nicotine‑treated mice displayed a biologically younger phenotype.

This study provides the first systemic mapping of nicotine‑driven metabolic remodeling during natural aging, and identifies a gut-sphingolipid-energy axis underlying motor function resilience. It makes a life‑long, dose‑dependent assessment of nicotine's systemic impact, integrates AI-based 3D behavioral and multi‑omics data to quantify biological aging, and provides insight into sphingolipid‑mediated neuromuscular protection.

Researchers note that while oral nicotine in this controlled paradigm avoids combustion‑related toxicants and may pose lower systemic risks than conventional tobacco products, its long‑term safety and complex biological effects warrant careful evaluation. The study provides a mechanistic framework to evaluate long‑term nicotine exposure and inspires the development of "non‑addictive cholinergic metabolic modulators" aimed at sustaining mobility and metabolic health in aging populations.

Building on years of expertise in metabolism, neurobiology, and inhalable materials, the research team will continue making systematic, forward‑looking research to uncover the scientific basis and potential value of nicotine as well as novel aerosolized compounds in aging intervention and metabolic health.