Calorie Restriction Suppresses the Senescence-Associated Secretory Phenotype
The accumulation of senescent cells is one of the causes of aging, important in the chronic inflammation of aging, and disruptive of tissue structure and function. The practice of calorie restriction slows the progression of aging, much more so in short-lived animals than in long-lived species, and thus we should expect it to have some effect on cellular senescence. Calorie restriction is nowhere near as effective as senolytic drugs at reducing the populations of senescent cells present in older individuals, that much is evident from studies carried out in recent years. As noted here, however, it does appear to somewhat reduce the inflammatory signaling generated by senescent cells.
Chronic inflammation, a pervasive feature of the aging process, is defined by a continuous, multifarious, low-grade inflammatory response. It is a sustained and systemic phenomenon that aggravates aging and can lead to age-related chronic diseases. In recent years, our understanding of age-related chronic inflammation has advanced through a large number of investigations on aging and calorie restriction (CR). A broader view of age-related inflammation is the concept of senoinflammation, which has an outlook beyond the traditional view.
Senescent cells produce a proinflammatory senescence-associated (SA) secretome, which is referred to as the SASP. Macrophages are recruited by chemotactic factors in the secretome to clear senescent cells. However, senescent macrophages secrete proinflammatory cytokines and exhibit impaired phagocytosis and chemotaxis, and a downregulated rate of cellular proliferation. It has been proposed that deficiency in the ability of aged macrophages to clear senescent cells leads to increased inflammatory response and results in chronic inflammation as SASP plays a role in the initiation of tissue inflammation. Based on previous observations and evidence of the aging process at molecular and cellular levels, we coined the term senoinflammation to provide an expanded, broader view of age-related chronic inflammation and metabolic dysfunction.
Based on studies on senoinflammation and CR, we recognized that the senescence-associated secretory phenotype (SASP), which mainly comprises cytokines and chemokines, was significantly increased during aging, whereas it was suppressed during CR. Further, we recognized that cellular metabolic pathways were also dysregulated in aging; however, CR mimetics reversed these effects. Oxidative stress leads to improper gene regulation and genomic DNA damage during aging. Such improper gene regulation in aged senescent cells allows them to fall into a proinflammatory state, consequently changing systemic chemokine or cytokine activities. The proinflammatory SASP environment further exerts stress on the intracellular organelles, tissues, and systems, which affects the development and occurrence of metabolic disorders.
It appears that a repetitive vicious cycle occurs between SASP and metabolic dysregulation as proposed in the concept of senoinflammation, and this interactive network forms the basis of the aging process and age-related diseases. However, the secretion of proinflammatory mediators, collectively termed as SASP, in response to internal and external stress leads to the chronic inflammatory condition termed as senoinflammation. Based on CR experiments and observations, cytokine, chemokine, and metabolic pathways are significantly regulated by CR and CR mimetics in the aging process.