Academy

Cellular Senescence and Senotherapeutics

Cellular senescence is a permanent state of cell-cycle arrest that cells enter in response to various stressors such as DNA damage, telomere shortening, oxidative stress, or oncogenic signals. While senescence serves as a tumor-suppressive mechanism by halting the proliferation of damaged cells, the accumulation of senescent cells during aging contributes to chronic inflammation and tissue dysfunction.

Senescent cells secrete a complex mixture of pro-inflammatory cytokines, chemokines, growth factors, and proteases collectively known as the senescence-associated secretory phenotype (SASP). SASP factors alter the tissue microenvironment and can promote age-associated pathologies, including fibrosis, insulin resistance, and cancer progression. Targeting senescent cells or their deleterious secretions is therefore a promising strategy to improve healthspan and treat age-related diseases.

Senotherapeutics: Senolytics versus Senomorphics

Senotherapeutics are therapies designed to counteract the negative effects of cellular senescence. They fall into two main categories:

• Senolytics selectively induce apoptosis in senescent cells, reducing their burden in tissues. Examples include dasatinib and quercetin, which target anti-apoptotic pathways that senescent cells rely upon for survival.
• Senomorphics suppress SASP factor secretion without killing the cells. These agents aim to dampen inflammation and restore tissue homeostasis. Natural compounds like apigenin and resveratrol exhibit senomorphic properties by modulating inflammatory signaling pathways.

Mechanisms of Senomorphic Action

Senomorphic agents act by interfering with key signaling pathways that regulate SASP production, including:

• NF-κB and p38MAPK pathways: Central regulators of inflammatory cytokine expression.
• PI3K/Akt/mTOR signaling: Influences metabolic and stress response pathways that can drive SASP.
• Heat shock proteins (e.g., HSPA8): Chaperones that can modulate protein homeostasis and inflammatory signaling.

By binding to specific proteins—such as apigenin’s binding to PRDX6 and interference with HSPA8 crosstalk—senomorphics can attenuate multiple arms of the SASP network.

Applications and Future Directions

Senotherapeutics hold promise in treating a range of age-related and chronic diseases:

• Cancer therapy: Adjunctive use of senomorphics can sensitize tumors to chemotherapy and reduce treatment resistance.
• Fibrosis and chronic inflammation: Reducing SASP factors may alleviate organ fibrosis and inflammatory disorders.
• Neurodegeneration: Damping neuroinflammation could slow progression of Alzheimer’s and Parkinson’s diseases.

Future research should focus on identifying specific molecular targets, optimizing dosing and delivery, and conducting rigorous clinical trials to translate senotherapeutic strategies into safe and effective therapies for aging populations.