The process of aging is accompanied by numerous degenerative phenotypes. Muscles and bone break down, brain cells die, and overall physical ability deteriorates. One exception to this common trend of age-related degeneration is cancer, which results from a population of cells that survive through uncontrollable and unregulated proliferation.

Cells frequently enter the senescent stage when typical age-related phenomena, such as DNA damage, occur. (Nature Publishing Group)

Cells frequently enter the senescent stage when typical age-related phenomena, such as DNA damage, occur. (Nature Publishing Group)

If most tissue functions decline with age, how can one of deadliest age-related diseases (cancer) arise from cells that are too active? The work of Dr. Judy Campisi at the Buck Institute has found a potential link between these phenomena. Many age-related traits result from replicative senescence (also called cellular senescencefor more, see our blog on this topic), a process in which cells stop growing and dividing in response to stress. This process occurs as a safe guard to prevent the spread of aged or damaged DNA during mitosis (cell division). It was previously believed that senescent cells serve no purpose, but it’s now known that senescent cells secrete a number of pro-inflammatory cytokines, proteases, and growth factors that may contribute to the aging process. This phenotype is referred to as the senescence-associated secretory phenotype or SASP.

SASP is now under great scrutiny and scientists are avidly trying to determine its role and effects on surrounding tissues. SASP has been shown to induce cancer cell growth, thus providing a link between cellular decline and cancer with age. Knowing this connection, a key question is whether SASP-induced cancer formation can be prevented? Since senescence is a naturally occuring event, it can be inferred that it arose evolutionarily to serve a beneficial purpose. The pro-inflammatory cytokines and growth factors secreted by senescent cells heavily suggest a role in regenerating damaged tissue. Recent findings suggest that an early SASP factor, platelet-derived growth factor AA (PDGF-AA), is responsible for wound healing, and that the absence of this factor prevents healing. This raises a significant challenge for cancer research, SASP plays opposing roles: it has the essential function of inducing cell proliferation during wound healing, but it can also induce aging and death through the promotion of cancer tumor growth.

After senescence, cells secrete a number of factors that can contribute to cancer and aging. (Journal of Cell Biology)

After senescence, cells secrete a number of factors that can contribute to cancer and aging. (Journal of Cell Biology)

A number of approaches have been used to prevent the negative effects of SASP. DNA damage response proteins can induce SASP, and inactivating DNA repair mechanisms can potentially prevent SASP. The obvious problem with this strategy is that the DNA damage response is a critical component of cellular maintenance. Another approach is to eliminate senescent cells in various tissues. Interestingly, ablating senescent cells in mice does not affect lifespan but delays onset of age-associated diseases.

At the Buck Institute, Dr. Judy Campisi’s lab utilizes transgenic mouse and in vitro human cell models to identify and selectively clear senescent cells. The goal of her work is to answer questions about the benefits and drawbacks of senescent cell clearance. Dr. Campisi is also interested in understanding the molecular signals that regulate and inhibit SASP expression. A recently published study from the Campisi lab (see our interview of first author Remi Martin-Laberge) determined that suppression of MTOR activity through rapamycin treatment suppresses particular SASP-associated cytokine levels, especially IL1A. IL1A suppression hinders NF-κB activity, which is largely responsible for maintaining cell survival and inducing pro-inflammatory signals (including those found in SASP). This finding suggests that it’s possible to hinder SASP selectively. Additionally, the expression of particular microRNAs such as miR-146a and 146b is elevated in senescent cells. It is thought that these microRNAs might be part of a negative feedback loop to suppress the production of SASP factors such as Interleukins 6 and 8, and thus ectopic expression of these microRNAs can inhibit SASP signals.

Despite their benefits, cellular senescence and SASP clearly contribute to the aging process and cancer. Targeted approaches that eliminate senescent cells or SASP under specific circumstances appear to be the best possible method for preventing SASP-induced aging and disease without hindering the necessary wound healing effects that SASP also regulates. There is still much to be understood about cellular senescence and its purpose, however. Understanding how it occurs and the factors that regulate this process are paramount in revealing key mechanisms that contribute to aging and the onset of age-related diseases.