Abstract
Chronic undernutrition contributes to the increase in frailty observed among elderly adults, which is a pressing issue in the sector of health care for older people worldwide. Autophagy, an intracellular recycling system, is closely associated with age-related pathologies. Therefore, decreased autophagy in aging could be involved in the disruption of energy homeostasis that occurs during undernutrition; however, the physiological mechanisms underlying this process remain unknown. Here, we showed that 70% daily food restriction (FR) induced fatal hypoglycemia in 23–26-month-old (aged) mice, which exhibited significantly lower hepatic autophagy than 9-week-old (young) mice. The liver expressions of Bcl-2, an autophagy-negative regulator, and Beclin1–Bcl-2 binding, were increased in aged mice compared with young mice. The autophagy inducer Tat-Beclin1 D11, not the mTOR inhibitor rapamycin, decreased the plasma levels of the glucogenic amino acid and restored the blood glucose levels in aged FR mice. Decreased liver gluconeogenesis, body temperature, physical activity, amino acid metabolism, and hepatic mitochondrial dynamics were observed in the aged FR mice. These changes were restored by treatment with hochuekkito that is a herbal formula containing several autophagy-activating ingredients. Our results indicate that Bcl-2 upregulation in the liver during the aging process disturbs autophagy activation, which increases the vulnerability to undernutrition. The promotion of liver autophagy may offer clinical therapeutic benefits to frail elderly patients.
Highlights
As the world’s population ages, health care for older people has become a pressing issue
There were no significant differences in baseline levels of blood glucose between the two groups
After subjecting the mice to food restriction (FR), the blood glucose levels were considerably lower than baseline levels on day 5 and had partially recovered in young mice on day 10, but they continued to fall in the aged mice (Fig. 1a)
Summary
As the world’s population ages, health care for older people has become a pressing issue. Many factors, including impaired physical function, psychological disorders, and/or limited social interactions, may result in loss of appetite and/or decreased food intake among the elderly. A pooled analysis of data from older people aged 65 years and over in hospitals in 12 countries reported that 39% were at nutritional risk[1]. Undernutrition leads to frailty, longer hospital stays, frequent readmission, and higher mortality in elderly patients[2,3,4]. Impaired autophagy is closely related to the development of several age-related disorders, including cancer, as well as cardiovascular and neurodegenerative diseases[9]
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