Role of dietary amino acid balance in diet restriction‐mediated lifespan extension, renoprotection, and muscle weakness in aged mice

Summary Extending healthy lifespan is an emerging issue in an aging society. This study was designed to identify a dietary method of extending lifespan, promoting renoprotection, and preventing muscle weakness in aged mice, with a focus on the importance of the balance between dietary essential ( EAA s) and nonessential amino acids ( NEAA s) on the dietary restriction ( DR )‐induced antiaging effect. Groups of aged mice were fed ad libitum, a simple DR , or a DR with recovering NEAA s or EAA s. Simple DR significantly extended lifespan and ameliorated age‐related kidney injury; however, the beneficial effects of DR were canceled by recovering dietary EAA but not NEAA . Simple DR prevented the age‐dependent decrease in slow‐twitch muscle fiber function but reduced absolute fast‐twitch muscle fiber function. DR ‐induced fast‐twitch muscle fiber dysfunction was improved by recovering either dietary NEAA s or EAA s. In the ad libitum‐fed and the DR plus EAA groups, the renal content of methionine, an EAA , was significantly higher, accompanied by lower renal production of hydrogen sulfide (H 2 S), an endogenous antioxidant. Finally, removal of methionine from the dietary EAA supplement diminished the adverse effects of dietary EAA on lifespan and kidney injury in the diet‐restricted aged mice, which were accompanied by a recovery in H 2 S production capacity and lower oxidative stress. These data imply that a dietary approach could combat kidney aging and prolong lifespan, while preventing muscle weakness, and suggest that renal methionine metabolism and the trans‐sulfuration pathway could be therapeutic targets for preventing kidney aging and subsequently promoting healthy aging.