Cellular senescence’s silver lining

New study shows that cellular senescence plays a critical role in the prevalence of cancer – and why balance is key.

Cellular senescence is a stress response that occurs mostly due to factors that trigger damage such as DNA damage, aging, reactive oxygen species, activation and inactivation of certain genes or inflammatory cytokines. Characterization of senescence can take place through four basic hallmarks – irreversible cell-cycle arrest, macromolecular damage, a senescence-associated secretory phenotype (SASP) and altered metabolism [1].

Cellular senescence is often cast as a longevity ‘baddie’ – after all, it can lead to reduced tissue repair and regeneration, accelerated aging, chronic inflammation, exhaustion of stem cells and immune deficit [2]. However, as so often in biology, there is another side to things; cellular senescence can also have beneficial functions such as wound healing, tumor suppression, regulation of embryonic development and resolution of fibrosis.

Senescence can impact several regulatory pathways. Many such pathways are associated with cancer development, progression, suppression, recurrence and response to treatments.

Cancer, which is currently the second most common cause of death globally among humans and led to the death of approximately 10 million people in 2020 [3], arises when normal cells turn into tumor cells either in response to genetic factors or external factors. Cellular senescence can prevent the proliferation of cancer cells (since senescent cells no longer replicate) and suppress malignant progression from a pre-malignant state to a malignant disease.

Lifespan and cancer are inextricably intertwined; the incidence of cancer most often increases with age. This is due in part to the accumulation of genetic mutations and other cellular changes that occur over time, leading to an increased risk of cancer development. Additionally, as we age, our immune system becomes less effective at recognizing and destroying cancer cells, which can allow them to grow and spread.

Significant investments in cellular and molecular research have helped to reduce mortality among cancer patients over the years, but there is still much work to be done – the relationship between aging and cancer underscores the importance of understanding the role cellular senescence plays in promoting and preventing cancer.

Longevity.Technology: Many theories indicate that cancer results due to the accumulation of epigenetic and genetic alterations. Such theories have been verified multiple times and report that healthy cells can turn into cancer cells after the accumulation of 4 to 10 mutations under positive selection. They can provide certain predictions such as long-lived and larger animal species should have a higher risk of cancer – the so-called Peto’s Paradox – but they are not supported by empirical data.

Previous research also highlights the incidence of most cancers in humans and dogs increases with age but only until a point following which its incidence declines [4]. However, most hypotheses have reported this to be a population bias since little data is available to support this observation.

Research published in Evolutionary Applications analyzed whether cellular senescence is capable of explaining the species and population pattern of cancer prevalence as well as its decrease in incidence with age.

“An organism favoring the entrance of damaged cells into senescence should therefore suffer from reduced levels of carcinogenesis,” says the team of researchers [5].

Whether cellular senescence can be an adaptation for cancer is unknown; however, research indicates that senescent cells could lead to actuarial aging and age-related disorders. This could mean that a trade-off could emerge where organisms could trade off one cause of death (cancer) for others (age-related disease). Apoptosis is another pathway that can decrease the mortality of organisms through the removal of damaged cells. However, it can lead to additional mutations and greater stem cell exhaustion, thereby increasing the risk of cancer.

This study built a model to analyze whether damaged cells undergo apoptosis or senescence. It also uses “Lifetime Reproductive Success” (LRS) to incorporate reproductive senescence and extrinsic mortality.

Accumulation of senescent cells led to the increase in LRS by more than 1 percent which was mostly influenced by the organism’s or tissue’s intrinsic parameters. A deceleration in 33 percent of cases and a decline in 15 percent of the cases were also observed which was influenced by the extent of external mortality [5].

An increase in the size of an organism was reported with a decrease in cancer prevalence due to a larger accumulation of senescent cells with age. Moreover, the killing of senescent cells at any age increased the risk of cancer.

“We show that under a simple set of equations, the hypothesis that cellular senescence is adaptive could be validated and that predictions for further empirical studies can be drawn,” says the team of researchers, who concluded that: “cellular senescence can optimize lifetime reproductive success [and that] life-history traits play an important role in shaping the cellular trade-offs [5].”

Senolytics – compounds that selective kill senescent cells – might allow us to have the best of both worlds. Senescent cells could supress cancer that originates from cell damage but then be targeted and destroyed before they have a chance to emit dangerous levels of SASP. Will science be able to determine the ‘optimum healthy level’ of senescence? Time will tell.

[1] https://jeccr.biomedcentral.com/articles/10.1186/s13046-022-02555-3
[2] https://www.nature.com/articles/s41581-022-00601-z
[3] https://www.who.int/news-room/fact-sheets/detail/cancer
[4] https://pubmed.ncbi.nlm.nih.gov/12074288/
[5] https://pubmed.ncbi.nlm.nih.gov/36969142/

Photograph: Freepik