Autophagy in the Heart and Liver During Normal Aging and Calorie Restriction

Abstract

Autophagy is a highly regulated intracellular process for the degradation of cellular constituents and essential for the maintenance of a healthy cell. We evaluated the effects of age and life-long calorie restriction on autophagy in heart and liver of young (6 months) and old (26 months) Fisher 344 rats. We observed that the occurrence of autophagic vacuoles was higher in heart than liver. The occurrence of autophagic vacuoles was not affected by age in either tissue, but was increased with calorie restriction in heart but not in liver. Next, we examined the expression of proteins involved in the formation and maturation of autophagosomes (beclin-1, LC3, Atg7, Atg9) or associated with autolysosomes and lysosomes (LAMP-1; cathepsin D). In hearts of both ad libitum-fed and calorie-restricted rats, we observed an increase in expression of beclin-1 and procathepsin D, but not mature cathepsin D, and a decrease in expression of LAMP-1 because of aging. In hearts, calorie restriction stimulated the expression of Atg7 and Atg9 and the lipidation of Atg8 (elevated LC3-II/I ratios) in aged rats. In hearts of ad libitum-fed rats, expression of Atg7 and lipidation of Atg8 were unaffected by age, while the cellular levels of Atg9 were lower in aged animals. Furthermore, we observed that the age- and diet-dependent expression levels of those proteins differed between heart and liver. In conclusion, autophagy in heart and liver did not decrease with age in ad libitum-fed rats, but was enhanced by calorie restriction in the heart. Thus, calorie restriction may mediate some of its beneficial effects by stimulating autophagy in the heart, indicating the potential for cardioprotective therapies.

Age-related changes in the function of autophagy in rat kidneys

“…In this study, we found that expression of Atg7 and LC3/Atg8 was significantly decreased in aged rat kidneys, whereas there was no marked change in the expression of Atg5. These results are consistent with a previous study that reported a decrease in Atg7 expression in older rat hearts (Wohlgemuth et al 2007). Isolated mitochondria obtained from Atg7 −/− skeletal muscle cells exhibit a significant defect in mitochondrial respiration, indicating that there is a close relationship between autophagy, oxidative stress, and aging (Wu et al 2009a).…”

“…In addition, we also indicated that protein expression of beclin-1/Atg6 was slightly but not significantly increased in the aged rat kidneys, which is in line with the earlier report (Kume et al 2010). Previous studies have found that beclin-1 has a significant increase in the aged rat heart (Wohlgemuth et al 2007) and skeletal muscle (Wohlgemuth et al 2010). Changes in beclin-1 are tissue and cell context dependent.…”

“…6 a, intimate relationship between autophagy and the aging process (Hara et al 2006;Komatsu et al 2005;Nakai et al 2007). Although it is known that autophagy decreases with age in the liver (Wohlgemuth et al 2007), the effects of aging on autophagy in the mammalian kidneys have not yet been elucidated.…”

“…It has been postulated that those dysfunctional mitochondria may undergo further oxidative damage, resulting in increased ROS production and decreased energy production (Terman et al 2003). These results suggest that deficiency in autophagy leads to an accumulation of damaged mitochondria (Wohlgemuth et al 2007;Kume et al 2010;Tong et al 2010). There is growing evidence that the efficiency of the degradative system involved in mitochondrial turnover declines with age.…”

Mitochondrial damage-induced impairment of angiogenesis in the aging rat kidney

“…28 However, there is a contradicting report that autophagy in the heart and liver do not decrease with age in ad libitum-fed rats and is enhanced by caloric restriction in the heart. 29 There are few reports examining autophagy in the aging kidney. Our examination showed that the expression of beclin 1, which has a significant role in autophagy, 30 was increased compared with that in young rat kidney (Supplementary Figure 3).…”