Decline in Liver Mitochondria Metabolic Function Is Restored by Hochuekkito Through Sirtuin 1 in Aged Mice With Malnutrition

Abstract

Malnutrition impairs basic daily activities and leads to physical frailty, which is aggravated in the elderly compared with young adults. It is also well-known that the elderly are more vulnerable to metabolic stress. Therefore, in this study, using a food restricted (FR) mouse, we aimed to evaluate the effect of aging on locomotor activity and liver metabolic function. Further, we also investigated the involvement of hepatic mitochondria in liver metabolic function during aging, as well as the therapeutic benefit of the traditional Japanese medicine, hochuekkito (HET). Our findings indicated that following food restriction provided as 30% of ad libitum intake for 5 days, the locomotor activity was lower in 23–26-month-old (aged) mice than in 9-week-old (young) mice. Further, compared with young mice, aged mice exhibited significant decreases in the levels of metabolites related to the urea cycle, mitochondrial function, and anti-oxidative stress. The livers of the aged mice also showed a greater decrease in mitochondrial DNA copy number than young mice. Furthermore, the gene expression levels of sirtuin 1 (SIRT1) and mitochondrial biogenesis-related regulators were attenuated in aged mice. However, these changes were partially restored by HET treatment, which also improved locomotor activity, and combined treatment with alanine resulted in more significant effects in this regard. Therefore, our findings suggested that the decrease in locomotor activity in aged FR mice was associated with a decline in the metabolic function of hepatic mitochondria via decreased SIRT1 expression, which was restored by HET treatment. This implies that enhancing the metabolic function of liver mitochondria can contribute to alleviating energy deficiency in the elderly.

Metabolic modeling reveals the aging-associated decline of host-microbiome metabolic interactions in mice

“…On the host side, we found appreciable conservation of aging-associated changes across tissues, including the induction of inflammatory processes and suppression of cellular replication, consistent with the conserved signature of aging that we identified previously 3 . Our results for the individual organs were also consistent with prior observations, including altered gut motility (linked to enteric neurons) 73,74 , reduced colonic barrier function 14 , reduced proliferative potential 75 , and altered mitochondrial morphology and reduced mitochondrial DNA in the liver of aged mice 76 .…”

MICOS Complex Loss Governs Age-Associated Murine Mitochondrial Architecture and Metabolism in the Liver, While Sam50 Dictates Diet Changes

“…In aged murine liver, decreases in the mtDNA numbers, urea cycle, mitochondrial function, locomotor activity, loss of enzymatic activity, and anti-oxidative stress are well established (123, 125, 126). Mitochondria also show diminished membrane potential across aging in murine liver (127) and declined mitophagy responses (128).…”