Age-related kidney dysfunction impairs the kidney's response to stressors, increasing the risk of renal failure and other kidney diseases. Renal ageing is characterized by interstitial fibrosis, tubular atrophy, reduced cortical mass and increased glomerulosclerosis. To date, there are no pharmacological remedies to halt or prevent age-related kidney ageing. Recent studies suggest that alterations in pathways involved in proteostasis: p53/p21CIP1, p16INK4a/Rb, mTOR and AMPK, contribute to cellular senescence and inflammatory/ profibrotic profiles. Accordingly dietary elements supporting protein synthesis and homeostasis may contrast multiple aspects of cellular senescence. Based on previous findings that branched-chain amino acid supplementation alone (mix1) or in combination with two equivalents of L-alanine (mix2) or the dipeptide L-alanyl- L- alanine (mix3), improves muscle function in mouse models of physiological aging [1,2], we aimed to investigate the effects of these supplements on age-related renal fibrosis. Oral formulations of mix1, mix2, mix3 were administered in 70-week- old C57BL/6 (AGED) male mice for 12 weeks in drinking water at doses and schedules previously described [1,2]. Treatment outcomes were assessed using ex vivo readouts (histological staining, qRT-PCR) compared to untreated AGED and ADULT (12-week- old) mice. Histomorphological analysis by H&E staining revealed typical age-related kidney alterations in untreated AGED mice vs. ADULT. An increase of tubulo-interstitial fibrosis was found by Sirius Red and Fast Green staining and measured as the ratio of number of strong positive over the total area analyzed. The treatments, particularly mix2, significantly reduced collagen deposition and unhealthy tissue (fold change = 2.4, p = 0.01). qRT-PCR showed increased expression of inflammation-related genes (NF-kB1, IL-1β, TGF-β1, TNF-α, NOS3) in AGED kidneys, which were significantly downregulated by all treatments, with mix2 showing the most effective reduction (over 58%). Branched-chain amino acid supplementation may prevent age-related renal fibrosis. These findings highlight the importance of nutritional interventions in renal ageing.
Branched-chain amino acid supplementation in a mouse model of ageing: Effects on age-related kidney fibrosis
Roberta Lenti;Paola Pontrelli;Paola Mantuano;Brigida Boccanegra;Alberto Ladisa;Antonella Liantonio;Loreto Gesualdo;Michela De Bellis;Annamaria De Luca
2025-01-01
Abstract
Age-related kidney dysfunction impairs the kidney's response to stressors, increasing the risk of renal failure and other kidney diseases. Renal ageing is characterized by interstitial fibrosis, tubular atrophy, reduced cortical mass and increased glomerulosclerosis. To date, there are no pharmacological remedies to halt or prevent age-related kidney ageing. Recent studies suggest that alterations in pathways involved in proteostasis: p53/p21CIP1, p16INK4a/Rb, mTOR and AMPK, contribute to cellular senescence and inflammatory/ profibrotic profiles. Accordingly dietary elements supporting protein synthesis and homeostasis may contrast multiple aspects of cellular senescence. Based on previous findings that branched-chain amino acid supplementation alone (mix1) or in combination with two equivalents of L-alanine (mix2) or the dipeptide L-alanyl- L- alanine (mix3), improves muscle function in mouse models of physiological aging [1,2], we aimed to investigate the effects of these supplements on age-related renal fibrosis. Oral formulations of mix1, mix2, mix3 were administered in 70-week- old C57BL/6 (AGED) male mice for 12 weeks in drinking water at doses and schedules previously described [1,2]. Treatment outcomes were assessed using ex vivo readouts (histological staining, qRT-PCR) compared to untreated AGED and ADULT (12-week- old) mice. Histomorphological analysis by H&E staining revealed typical age-related kidney alterations in untreated AGED mice vs. ADULT. An increase of tubulo-interstitial fibrosis was found by Sirius Red and Fast Green staining and measured as the ratio of number of strong positive over the total area analyzed. The treatments, particularly mix2, significantly reduced collagen deposition and unhealthy tissue (fold change = 2.4, p = 0.01). qRT-PCR showed increased expression of inflammation-related genes (NF-kB1, IL-1β, TGF-β1, TNF-α, NOS3) in AGED kidneys, which were significantly downregulated by all treatments, with mix2 showing the most effective reduction (over 58%). Branched-chain amino acid supplementation may prevent age-related renal fibrosis. These findings highlight the importance of nutritional interventions in renal ageing.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
