Perspectives on cellular senescence and short term dietary restriction in adults

an important study in this journal, Wang et al. found short term dietary restriction in middle-aged mice is associated with decreased abundance of senescent cells in the liver (centrilobular hepatocytes) and intestine (crypt enterocytes) [1]. They detected this reduction following 3 months of 26% caloric restriction in 17 month old mice by assaying cellular γH2AX, a protein that associates with damaged DNA, PCNA, an indicator of replication, and senescence-associated β-galactosidase (SA β–gal). The relatively short period of caloric restriction resulted in a 3.3 to 6.5% decrease in senescent cell abundance as a function of total cell number. Despite similar or lower telomerase activity in the calorically restricted compared to ad libitum-fed mice, average telomere length in crypt enterocyte nuclei was greater in the calorically restricted animals. The telomere preservation could have been a result of reduced ROS in the calorically restricted animals, since ROS accelerate telomeric DNA loss. Consistent with this possibility, the authors found that markers of cellular oxidative damage (4-HNE and broad-band autofluorescence) were lower in the cell types in which senescence was reduced in the calorically restricted mice. Additional experiments need to be done to test if the association between reduced oxidative damage following short term caloric restriction and decreased senescence reflects a causal relationship. The authors suggest that reduced cellular senescence might be a primary effect of caloric restriction. They speculate this could be mediated through suppression of signaling through mTOR and S6K1, and that this might contribute to improved mitochondrial function and reduced ROS. These possibilities need to be tested directly in future studies. As with many interesting studies, this study raises many more questions than it answers. Several of these questions, their potential implications, and suggestions Commentary on for further study follow. Does short term caloric restriction reduce the proportion of senescent cells in other tissues, such as fat? Obesity, aging, and other conditions are associated with extensive accumulation of senescent cells in fat tissue of rodents as well as humans, in whom fat is frequently the most abundant tissue in the body [2-4]. Fat tissue becomes inflamed in association with senescent cell accumulation, potentially leading to clinically important systemic consequences such as diabetes and atherosclerosis. Fat tissue is also among the first tissues to be affected structurally and metabolically by caloric restriction, so determining the impact of short term caloric restriction on fat tissue cellular senescence is particularly important. It would also be …