Friday, June 7, 2019

Senescent Cells and Human Longevity

Although the average human lifespan has increased substantially over time due to the improvement in living conditions made possible by advances in public health, sanitation, medicine, etc., there is no selective advantage afforded by a longer life once the reproductive period has passed. Consequently, there is a normal and gradual deterioration of the tissues that is age-related.

Furthermore, there is a natural process referred to as cellular senescence – cells undergoing this change are no longer able to divide. Cellular senescence confers a reproductive advantage for the individual in that it helps block cancer cell proliferation; however, overtime it results in an increasing abundance of senescent cells (SNC) within the tissues. It seems that in animal studies, using the mouse model, in which the SNCs are selectively eliminated (senolysis),the median lifespan of individual test mice is extended, and the frequency of age-related diseases has been shown to be diminished. This result has encouraged the search for and development of drugs that selectively target SNCs.

In terms of this research, it is vitally important to discover the actual mechanisms that underly cellular senescence. In studies using cells grown in culture, it has been shown that SNCs are in a state of permanent cell cycle arrest. This state is apparently initiated and maintained by the p53-p21 retinoblastoma (RB) and p16-RB tumor suppressor pathways. The factors that can trigger this process are –
  • Oxidative stress
  • Shortening to telomeres – repetitive DNA sequences at the ends of chromosomes that afford protection
  • Prolonged mitotic activity
  • DNA errors during replication
  • Mitochondrial impairment.
SNCs produce a so-called, “Senescence associated secretory phenotype” (SASP). SASP has been shown to negatively impact normal tissue architecture through a variety of processes including the onset of fibrosis and the inhibition of stem cell functionality. Although SASP has a protective function in regard to the development of cellular neoplasm, in later life it does not seem to provide a protective function against the onset of cancer. This raised the possibility that the selective elimination of SNCs from older patients might exert an anti-cancer effect.

Given this data, it would seem that therapies that can effectively eliminate SNCs might produce a two-fold health advantage by increasing longevity and by decreasing the onset of cancer in later life. Encouraging results from animal model studies have shown that drugs that target those pathways that block apoptosis – programmed cell death – promote senolysis and afford an anti-cancer potential. In regard to future research, this may provide a very fruitful line of enquiry.