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

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 (EAAs) and nonessential amino acids (NEAAs) on the dietary restriction (DR)-induced antiaging effect. Groups of aged mice were fed ad libitum, a simple DR, or a DR with recovering NEAAs or EAAs. 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 NEAAs or EAAs. 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 (H2 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 H2 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.

Altered unfolded protein response is implicated in the age-related exacerbation of proteinuria-induced proximal tubular cell damage.

Aging is a dominant risk factor for end-stage renal disease. We analyzed the mechanism involved in age-related exacerbation of proteinuria-induced proximal tubular cell (PTC) damage by focusing on endoplasmic reticulum-related unfolded protein response (UPR). After equal-degree induction of proteinuria in 24-month-old (aged) and 3-month-old (young) mice by intraperitoneal free fatty acid-bound albumin overload, tubulointerstitial lesions were more severe in aged than in young mice. In aged PTCs, proteinuria-induced cell-adaptive UPR resulting from induction of the molecular chaperone BiP was significantly suppressed, whereas proapoptotic UPR with CHOP overexpression was enhanced. Treatment with the exogenous molecular chaperone tauroursodeoxycholic acid (TUDCA) ameliorated proteinuria-induced tubulointerstitial lesions and PTC apoptosis in aged mice. Among the three UPR branches, alterations in the inositol-requiring 1α (IRE1α) pathway, but not the activating transcription factor 6 or PERK pathway, were associated with impaired BiP induction in aged kidneys. Moreover, siRNA-mediated suppression of BiP and IRE1α exacerbated free fatty acid-bound albumin-induced apoptosis in cultured PTCs, whereas siRNA-mediated CHOP suppression ameliorated apoptosis. Finally, proteinuria-induced BiP induction in PTCs was diminished in kidney specimens from elderly patients. These results indicate that maladaptive UPRs are involved in proteinuria-induced tubulointerstitial lesions exacerbation in aged kidneys, and that supplementation of chaperones may be used to treat elderly patients with persistent proteinuria. These results should improve understanding of cell vulnerability in aged kidneys.