An Approach to Reducing the Senescence-Associated Secretory Phenotype in Aged Tissues
Senescent cells accumulate with age in tissues throughout the body, an important contribution to age-related dysfunction and disease. On entering the senescent state, a cell ceases to replicate and begins to energetically secrete a pro-inflammatory mix of signals, rousing the immune system to action. In youth, cellular senescence serves useful purposes, such as coordination of regeneration from injury and removal of potentially cancerous cells. In the young, senescent cells are removed rapidly by the immune system, preventing their accumulation. With advancing age, the balance between creation and destruction shifts and a population of lingering senescent cells grows over the years. The inflammatory signals that are useful in the short term become harmful when sustained over the long term, a major contribution to the characteristic chronic inflammation of old age.
While most efforts targeting cellular senescence are focused on ways to selectively destroy these errant cells in aged tissues, a smaller faction of the research community is more interested in finding ways to reduce the secretion of inflammatory signals. In principle, the presence of senescent cells would cause comparatively little harm provided their inflammatory signaling was greatly reduced. One can look at cellular senescence in the long-lived naked mole-rats as a model for this desired goal, as senescent cells in that species do not produce anything like the same degree of inflammatory signaling. There is no way as yet to produce a similar degree of reduced inflammatory signaling in mice, but researchers continue to look for a viable approach.
In response to various stimuli, senescent cells (SnCs) accumulate in aging tissues, and this occurs in parallel with chronic inflammation and age-related functional decline. SnCs are normally rare in most tissues, suggesting that the ripple effect of the senescence-associated secretory phenotype (SASP) amplifies pro-inflammatory signaling in the senescent microenvironment. Because the processes of de novo protein production and secretion consume a lot of cellular energy, unique strategies must exist to collaboratively regulate gene expression, the epigenome, and metabolism.
During the senescent transition of the cells, senescence-associated phenotypes are shaped entirely through epigenomic and metabolic coregulation. The expression of cyclin-dependent kinase inhibitor p16, one of the biomarkers for SnCs, is induced. Activation of the p16-retinoblastoma protein (RB) pathway not only causes cell-cycle arrest but also triggers metabolic reprogramming of glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) by upregulating glycolytic enzymes and the pyruvate dehydrogenase phosphatase 2 that augments the active form of pyruvate dehydrogenase. Since the resulting metabolites, such as S-adenosylmethionine, α-ketoglutarate (αKG), and acetyl-coenzyme A (CoA), are used for adjusting the activities of epigenome modifiers, they further affect the epigenomic state that defines the transcriptional program of SnCs. However, molecular specificity for SASP-related pro-inflammatory gene regulation has not been convincingly established.
Citrate plays important roles in energy production, macromolecular biosynthesis, and protein modification. Within the mitochondria, citrate is generated from acetyl-CoA and oxaloacetate by the citrate synthetase and serves as a substrate in the tricarboxylic acid (TCA) cycle that produces essential metabolites for OXPHOS. In addition, citrate is exported from mitochondria to the cytoplasm and subsequently cleaved by ATP-citrate lyase (ACLY), which generates acetyl-CoA and oxaloacetate. Acetyl-CoA derived from this unique reaction, so called the non-canonical TCA cycle pathway, acts as a source for various metabolic functions, including fatty acid synthesis and the mevalonate pathway, and protein acetylation. Although recent studies have shown that ACLY inhibition improves metabolic health and physical strength in obese mice the role of the non-canonical TCA cycle pathway mediated by ACLY in SnCs remains totally unknown.
Here, we show that ACLY is essential for the pro-inflammatory SASP, independent of persistent growth arrest in senescent cells. Citrate-derived acetyl-CoA facilitates the action of SASP gene enhancers. ACLY-dependent de novo enhancers augment the recruitment of the chromatin reader BRD4, which causes SASP activation. Consistently, specific inhibitions of the ACLY-BRD4 axis suppress the STAT1-mediated interferon response, creating the pro-inflammatory microenvironment in senescent cells and tissues. Our results demonstrate that ACLY-dependent citrate metabolism represents a selective target for controlling SASP designed to promote healthy aging.