Cellular Senescence

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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).

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

 

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