Summary
- Introduction.
- Causes of Senescent Cells.
- Process of Senescent Cells Generation.
- Senescence-Associated Secretory Phenotype (SASP).
- Effect of Build-up of Senescent Cells.
- mTOR and Senescence.
- Role of Telomeres.
- Potential Fixes.
- Sources and Links.
Introduction
- Normal cells cease to divide.
- Maximum of approximately 50 doublings before becoming senescent (“Hayflick limit”).
- In other words, cells are “mortal” (in terms of proliferation).
- Irreversible arrest of cell proliferation.
- Only immortal cultured cells are cancer cells.
- Key senescence functions:
- Tumor suppression mechanism (avoid spread of mutated DNA).
- Promoter of tissue remodeling after wounding (promote immune response).
- Generally a response to environmental stress.
- DNA damage.
- Cellular senescence, autophagy, and apoptosis all are cellular responses to stress.
- Senescent cells (SC) no longer replicate, but remain metabolically active, resulting in:
- Increased cell size and mitochondrial mass.
- Mitochondrial dysfunction.
- Secretion of pro-inflammatory and pro-oxidant signals.
- Failure of full autophagy (avoiding cell death).
- mTORC1 related to senescence in number of ways:
- mTORC1 may drive creation of SC (by slowing down autophagy, allowing damaged cells to stick around and become senescent).
- mTORC1 may keep SC around longer (by slowing down autophagy, preventing SC cell death).
- Normally, SC are destroyed through apoptosis or removed by immune system.
- Clearance of SC proven to improve both health- and life-span.
- Number of SC in tissues increases with age.
- Due to less effective immune surveillance.
- Build-up of SC causes chronic inflammation and surrounding cell damage.
- Contributes to age-related diseases.
- Evolutionary trade-off: SC beneficial (tumor suppressive, wound repair) and detrimental (pro-aging).
- Good early in life in small numbers.
- Bad late in life in larger numbers.
Causes of Senescent Cells
- Triggered by:
- DNA damage.
- Shortening of telomeres during cellular division process.
- Increased activity of elevated reactive oxygen species (ROS).
- Activation of oncogenes.
- High concentration of glucose.
- Mitochondrial dysfunction.
Process of Senescent Cells Generation
- Cellular stress events result in the activation of the tumor suppressor protein p53.
- Drives the production of two cell-cycle dependent kinase inhibitors (CDK inhibitors) p21 and p16.
- P21 and p16 are required for the establishment and subsequent maintenance of the senescent cell state.
- P21
- Produced first.
- Initial p21-driven signal is an acute response to cell damage.
- Blocks the production of numerous proteins that cells need to divide.
- Eventually decreases.
- P16
- Permanently locks the cell into a non-dividing state.
- Production of p16 continues as long as the cell lives.
- Believed to be produced only in senescent cells.
- Widely used marker to identify and quantify senescent cells.
Senescence-Associated Secretory Phenotype (SASP)
- Once cells become senescent, they begin secreting large quantities of more than 100 proteins:
- Pro-inflammatory factors that recruit the immune system (cytokines).
- Proteases that remodel the extra-cellular matrix.
- Pro-fibrotic factors that drive the formation of dysfunctional matrix
- Growth factors that perturb the function of the tissue micro-environment.
- Collection of secreted proteins is referred to as the Senescence Associated Secretory Phenotype, or SASP(s).
- In addition to its effects on tissue function, the SASP contains factors that induce senescence in neighboring cells.
- Sets off a cascade of events that ultimately culminates in the formation of a functionally aged and/or diseased tissue that underlies a variety of age-associated diseases.
Effect of Build-up of Senescent Cells
- SC are typically destroyed through apoptosis or removed by immune system.
- SC build up due to a less effective immune surveillance over time.
- SC that survive express higher level of pro-survival genes (resisting apoptosis).
- Leads to spread of the SASP with a negative effect on neighboring cells and the surrounding tissue.
- The SASP may explain why a relative small amount of SC can have a large and systemic effect.
mTOR and Senescence
- SC continue to grow in size and send out pro-inflammatory signals.
- Mechanisms underlying these processes are not well understood.
- Various mechanisms seem to be supported by mTORC1 activity.
- In normal cells:
- mTOR activated by signals:
- Growth factors, energy and amino acid availability.
- mTOR ensures a tight balance of anabolic (protein translation, nucleotide synthesis) and catabolic (autophagy) processes.
- Under starvation of growth factors or amino acids:
- mTORC1 inhibited, autophagy activated.
- Shifts the cell from an anabolic to a catabolic program.
- Liberates nutrients and ensures cell survival.
- In SC:
- Growth factor and amino acid signals are absent.
- Absence should inhibt mTORC1 and increase autophagy.
- Autophagy increases enough for SC to survive.
- But, mTORC1 pathway seems to rewire (amino acid and growth factor sensing parts).
- mTORC1 remains active, preventing full autophagy and cell death.
- So, mTORC1 seems to play a role in keeping SC alive.
- Some research indicating that mTORC1 also plays a role in creating SC:
- Down-regulates autophagy.
- Damaged cells stick around and get worse.
- Over time, become SC.
- Depending on role of mTORC1, rapamycin may:
- Inhibit or delay cell senescence itself by increasing autophagy and driving down environmental stress.
- Inhibit, delay or dampen (SASP) impact of cell senescence (limiting cell biomass growth, pro-inflammatory signals).
- mTOR activated by signals:
Role of Telomeres
- The length of the telomere strand has senescent effects.
- Telomere shortening activates extensive alterations in alternative RNA splicing.
- Produce senescent toxins such as progerin.
- Degrades the tissue and makes it more prone to failure.
Potential Fixes
- Senolytics:
- Targets removal (apoptosis) of death-resistant senescent cells.
- Extending healthspan.
- Also alleviation wide range of pre-existent age-related symptoms including (CVD, etc.).
- Identifies survival pathways that SC rely on (different for types of tissue).
- Inhibits those pathways with specifically designed molecules so that SC undergo programmed cell death.
- Intermittent dosing may restore normal tissue function.
- Further drug administration would not be required until SC have re-accumulated.
- Rapamycin:
- Prevent SASP impact of SC (tissue damage).
- Potentially reduce SC creation.
- Metformin:
- Reduces SC creation through antioxidant protection and reduction of DNA damage.
- Also inhibition of SASP.
- Natural compounds may also dampen impact of SASP.
- Immune system boosters (to help improve immune surveillance and SC removal).
- Cell reprogramming (to re-activate proliferation).
Sources and Links
- mTOR as regulator of lifespan, aging and cellular senescence, Thomas Weichhart, Dec 2017, (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089343/)
- Dysregulation of mTORC1/autophagy axis in senescence, Carroll and Korolchuk, Aug 2017, (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5611974/)
- From ancient pathways to aging cells – Connecting metabolism and cellular senescence , Wiley, Jnu 2017, (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911819/)
- Therapeutic interventions for aging: the case of cellular senescence, Gamez and Demaria, May 2017, (https://www.sciencedirect.com/science/article/pii/S135964461730017X)