Path 8: Cellular Senescence

Rationale: Stopping the “zombie” cells that poison their neighbors. Senescent cells have permanently exited the cell cycle and secrete a cocktail of inflammatory and tissue-degrading molecules known as the SASP. Senescence helps prevent cancer but over time, senescent cells accumulate in tissues and drive chronic inflammation and dysfunction. If we can eliminate senescent cells (using “senolytic” drugs) or suppress their bad secretions, tissues might stay healthier longer.

Prerequisites: Cell biology (cell cycle, tumor suppression), immunology, pharmacology.

Dependencies: Ties with Path 3 (telomeres) since telomere shortening can trigger senescence, and Path 10 (inflammation) because senescent cells drive chronic inflammation. Also relates to Path 9 (stem cells).

Signs of Progress: Human clinical trials of senolytic drugs for age-related diseases. More refined senolytics targeting senescent cells specifically. Imaging techniques to quantify senescent cells in vivo. Senolytic strategies extending lifespan of a mammal substantially (mice ~+25–30% from periodic treatment).

BC8.1: Mechanisms of Cellular Senescence

Scope: Define cellular senescence: irreversible cell-cycle arrest with resistance to apoptosis and a pro-inflammatory secretome (SASP). Triggers: telomere shortening, DNA damage, oncogene activation, oxidative stress.

• Campisi, Judith. “Cellular senescence: putting the paradoxes in perspective.” Curr. Opin. Genet. Dev., 2011. – Explains the dual role: senescence prevents cancer but contributes to aging.
• Muñoz-Espín, D. & Serrano, M. “Cellular senescence: from physiology to pathology.” Nat. Rev. Mol. Cell Biol., 2014. – Comprehensive review of senescence mechanisms with nice diagrams.
• Hayflick, L. & Moorhead, P. “The serial cultivation of human diploid cell strains.” Exp. Cell Res., 1961. – Original Hayflick paper showing cell divisions petering out ~50 population doublings.

BC8.2: Senescence in Tissues and Aging

Scope: How senescent cells accumulate in tissues with age and in age-related diseases. Links to functional decline and impaired regeneration.

• van Deursen, Jan. “The role of senescent cells in ageing.” Nature, 2014. – Perspective by the scientist who created the first senolytic mouse model.
• Xu, M. et al. “Cellular senescence in aging and age-related diseases.” GeroScience, 2020. – Connecting accumulation of senescent cells to pathology in different organ systems.
• Baker, D.J. et al. “Clearance of p16^Ink4a^-positive senescent cells delays ageing-associated disorders.” Nature, 2011. – Groundbreaking mouse experiment: removing senescent cells delayed age pathologies.

BC8.3: The SASP and Inflammation

Scope: SASP components: pro-inflammatory cytokines, proteases, growth factors. SASP can spread senescence by bystander effect.

• Coppé, J.-P. et al. “The senescence-associated secretory phenotype: the dark side of tumor suppression.” Annu. Rev. Pathol., 2010. – Key review that coined “SASP” term.
• Prata, L. et al. “Senescent cell clearance by the immune system: Emerging therapeutic opportunities.” Semin. Immunol., 2018. – How the immune system deals with senescent cells.
• Basisty, N. et al. “A proteomic atlas of senescence-associated secretomes.” PLoS Biol., 2020. – Cataloguing SASP factors.

BC8.4: Senolytics and Other Therapeutic Approaches

Scope: Senolytics (Dasatinib+Quercetin, Navitoclax, Fisetin), senomorphics, gene therapies, CAR-T cells. Human pilot trials.

• Kirkland, J.L. et al. “The clinical potential of senolytic drugs.” J. Am. Geriatr. Soc., 2017. – Nice overview from Mayo Clinic team who pioneered senolytics.
• Zhu, Y. et al. “Identification of a novel senolytic agent, navitoclax.” Aging Cell, 2016. – One of the first senolytic discoveries after D+Q.
• Justice, J.N. et al. “Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human pilot study.” EBioMedicine, 2019. – First human trial of senolytics (Dasatinib+Quercetin in IPF patients).

Bibliography (Path 8)

• Campisi, Judith. “Cellular Senescence: Putting the Paradoxes in Perspective.” Curr. Opin. Genet. Dev. 21(1): 107–112, 2011. (Double-edged sword of senescence)
• Baker, Darren J. et al. “Clearance of p16^Ink4a^-Positive Senescent Cells Delays Ageing-Associated Disorders.” Nature 479(7372): 232–236, 2011. (Pioneering mouse study proving senescent cells drive aging pathologies)
• Xu, Ming et al. “Senolytics Improve Physical Function and Increase Lifespan in Old Age.” Nat. Med. 24(8): 1246–1256, 2018. (D+Q cleared senescent cells in naturally aged mice)
• Kirkland, James L. et al. “The Clinical Potential of Senolytic Drugs.” J. Am. Geriatr. Soc. 65(10): 2297–2301, 2017. (Overview of senolytics and potential human applications)
• He, Shenghui & Norman E. Sharpless. “Senescence in Health and Disease.” Cell 169(6): 1000–1011, 2017. (How senescent cells contribute to diseases and aging, balancing perspective)