Calorie Restriction Slows the Age-Related Accumulation of DNA Damage, Inflammation, and Cellular Senescence in Fat Tissue
The practice of calorie restriction slows near all measures of aging, slowing aging to a degree that appears to scale down with increased species life span. Calorie restricted mice live 40% longer, but calorie restricted humans are thought to at most gain five years or so - though a firm number has yet to be determined in our species. The short term changes to metabolism and benefits to health are nonetheless quite similar. As a companion piece to recent work on the effects of calorie restriction on cellular senescence, this open access paper makes for interesting reading. Senescent cells accumulate with age, and the damage they do to their environment via a potent mix of signal molecules is one of the root causes of aging and age-related disease. Unsurprisingly, calorie restriction slows this accumulation, just as it impacts all other processes of aging.
White adipose tissue (WAT) forms an endocrine organ with both positive and negative effects on metabolism. By secreting adipokines, adipocytes regulate metabolism, energy intake, and fat storage. Adipocytes are known to enlarge during obesity and the ageing process. In contrast, caloric restriction results in decreased body mass, and preferentially reduced the mass of different fat depots including up to 78% in visceral fat. Several studies demonstrated that increased fat cell size is a significant predictor of altered blood lipid profiles and glucose-insulin homeostasis. The contribution of visceral adiposity to these associations seems to be of particular importance.
Senescence and inflammation are two important mechanisms contributing to ageing and the metabolic consequences of obesity. Inflammation can result from accumulation of macrophages in adipose tissue via production of cytokines such as TNFα and IL-6. Increase in lipolysis has been shown to induce macrophage migration in vitro. Macrophage numbers in adipose tissue also increase with obesity and ageing where they scavenge dead or senescent adipocytes. However, inflammatory cytokines and chemokines are also characteristics of the senescence-associated secretory phenotype (SASP) in senescent cells. We have shown previously that reactive oxygen species (ROS), DNA damage, and mitochondrial dysfunction are instrumental to maintain cellular senescence.
Various treatments have been suggested to delay senescence in adipose tissues while obesity and short telomeres exacerbated senescence. A recent study showed that feeding a high-fat diet ad libitum induced senescence in mouse visceral adipose tissue which could be ameliorated by exercise. However, dietary restriction (DR) seems to regulate many more genes than exercise in subcutaneous fat in humans.
We have demonstrated previously that short-term dietary restriction in wild type mice decreased the amount of senescent cells in various tissues. We hypothesise that pro-inflammatory cytokines and senescence are also causally related in visceral WAT, increase together during ageing, and might be rescued during DR. We used visceral WAT from mice of different ages as well as mice on late-onset, short term DR to investigate the changes in adipocyte size, accumulation of DNA damage during ageing and DR, together with the expression of pro-inflammatory cytokines TNFα, IL-6, IL-1β, and senescence markers p16 and p21. We also analysed AMPK activity which is an important signal transduction pathway implicated in the regulation of physiological processes of DR. AMPK activation is thought to be able to inhibit inflammatory responses and plays a central role in the regulation of whole body energy homeostasis and functions as a key regulator of intracellular fatty acid metabolism.
Our results demonstrate increased senescence and inflammation during ageing in mouse visceral fat while DR was able to ameliorate several of these parameters. DR was able to significantly reduce adipocyte size and multiple markers of adipocyte senescence (significant for DNA damage, p21 and IL-6 expression). This indicates that DR acts as a senolytic treatment in visceral fat, similar to its effects in other tissues. This highlights the health benefits of a decreased nutritional intake over a relatively short period of time at middle age.