Based on the characteristics of the secretion of inflammatory cytokines released by aged cells the team hypothesizes that there are at least 4 distinct states of cellular senescence, and that these states arise from coordinated metabolic and epigenomic changes. The team believes that characterizing and categorizing qualitatively different states of cellular senescence could provide a new understanding of the aging and senescence processes.
World populations are aging at an accelerated rate, more so in developed countries. As the population of the elderly is expected to sharply increase in the near future it is especially important to maintain healthy lifespans.
Many of the cells that make up the body will eventually decline in function and stop growing after repeated divisions, and this cellular senescence is an important factor in health and longevity. However, premature senescence can occur when genomic DNA damage is caused by stressors like drugs, ultraviolet light, or radiation, but the mechanisms behind this are not yet fully understood. This process can be beneficial such as when cells become cancerous cellular senescence can work to prevent the development of malignancy, but it can also increase the likelihood of many age-related diseases, thus it is important for medical science to try to gain a better understanding to learn how to control it.
Although senescent cells lose their ability to proliferate, earning the nickname zombie cells, research shows that these cells secrete various proteins that act on surrounding cells/tissues and promote chronic inflammation and cancer cell growth. This process is called the senescence-associated secretory phenotype, and cellular senescence is believed to be the cause of aging in the entire body. Zombie cells have been shown to accumulate in the bodies of aged mice, and removal of these cells may suppress whole-body aging. In simple terms, if we can learn how to control cellular senesce we may be able to regulate the aging process of the entire body.
Professor Mitsuyoshi Nakao and associates are studying the mechanisms of cellular aging from the viewpoint of epigenetics, which is a field that investigates the activities of approximately 25,000 protein-encoding genes on the human genome, related to life phenomena, health, and disease conditions, and aging in humans. The team has screened a wide range of factors involved in the aging of human fibroblasts and found that SETD8 methyltransferase, NSD2 methyltransferase, and other proteins playing a role in preventing cellular senescence. The team was not able to discover any biomarker specific to senescent cells, leading the team to review cellular senescence over time and in terms of the characteristics of protein-secreting SASPs.
The team discovered that there are at least 4 phenotypic variations in cellular senescence:
- Initiation (proliferations arrest)
- Early ( anti-inflammation)
- Full (increased inflammation and metabolism)
- Late (decreased inflammation and metabolism)
Focusing on the molecular changes for each period the team showed that variations in cellular senescence may be shaped by a “senescent program” in which the change of intracellular metabolism and epigenomics takes place in a coordinated manner. The team then moved focus onto transcriptional and epigenomic factors that regulate the expression of genes that play important functions in the process of cellular senescence.
During the initiation state, genes that promote cell proliferation are suppressed while those that block proliferation are activated, and tumor suppressor proteins p53 and retinoblastoma play a major role in this process.
During the early state, cell morphology changes significantly, and cytokines with anti-inflammatory properties become activated, this may be a defense against the later inflammatory action.
During the full state, the genes of proinflammatory cytokines become highly expressed and produce a strong inflammatory response, while at the same time expression of metabolic genes such as mitochondria and genes that synthesize proteins are increased via the aforementioned retinoblastoma which was previously reported by this research group. Here, it is thought that metabolic reactions produce the energy needed to synthesize and secrete proteins.
Finally during the late state, the inflammatory response and metabolism decline, but interferon is produced and secreted in response to the cytoplasmic DNA fragments of the nuclear genome and mitochondrial DNA. While the mechanisms and significance of these processes are still not identified, it is now understood that cellular senescence results in a qualitatively different inflammatory response.
Processor Mitsuyoshi Nakao expressed: “We hope that our work will provide an opportunity for the scientific community to consider a new understanding of the mechanisms of cellular senescence and body aging. We believe that phenotypic variation in cellular senescence can lead to new methods to promote healthy longevity and the control and prevention of age-related diseases.”
