Low-dose lithium improved memory test performance and shifted markers of cellular clearance in old mice under metabolic stress

Low-dose lithium improved memory test performance and shifted markers of cellular clearance in old mice under metabolic stress

On August 26, the authors published a preprint describing a 16-week experiment in young and old male mice. A high-fat, high-calorie diet induced metabolic stress, and the animals received daily injections of lithium chloride at 10 mg/kg.

Each main group included ten animals. The metabolic stress diet caused greater impairment in old mice across three memory tests. Their hippocampi, brain regions involved in memory, also showed increased amyloid Aβ deposition, higher levels of phosphorylated tau protein, and elevated inflammatory markers. The authors describe these changes as pathology resembling Alzheimer’s disease.

The authors examined a pathway linking energy stress to cellular clearance. The enzyme NAMPT helps maintain the supply of NAD⁺, a molecule required for SIRT1 activity. SIRT1 and AMPK contribute to the cellular response to energy shortage. The protein TFEB regulates the formation of lysosomes, cellular compartments that break down damaged proteins and organelles.

In old mice fed the metabolic stress diet, NAMPT, NAD⁺, SIRT1 activity, and AMPK activity decreased, followed by reductions in TFEB and lysosomal proteins. Lithium shifted these measures toward the values observed in old mice fed standard chow and reduced inflammatory markers. In the water maze, where an animal must locate a hidden platform, old mice treated with lithium took approximately 37% less time to find it than mice of the same age fed the same diet.

A separate experiment tested the roles of SIRT1 and AMPK in this pathway. EX-527, an inhibitor of SIRT1, weakened the lithium-induced recovery of AMPK activity. Inhibition of either SIRT1 or AMPK also reduced the recovery of TFEB and the LC3-II/I ratio, a marker of autophagy, the process that recycles damaged cellular material. These results linked the changes associated with lithium to the cellular energy response and markers of lysosomal clearance in an aging mouse model.