CELL BIOLOGY AND GENETICS

LECTURE: CELL BIO

REGENERATIVE CAPACITY AND AGING

Decreased proliferation (multiplying)

● Of satellite cells (SCs) (adult stem cells) and myoblasts (progenitor cells - descendants of stem
cells that then further differentiate to create specialized cell types)
● Replicative senescence = Hayflick limit
● Senescence: The phase at which cells are alive but stop dividing even when treated with normal
growth factors that induce cell division is called
● Hayflick limit: the number of times a normal cell population divides before entering the
senescence phase

↓
Decrease in regenerative capacity/tissue homeostasis
↓
Impaired maintenance of tissue structure and function
↓
Aging

SOMATIC CELLS AND REPLICATIVE SENESCENCE

● A cell population reaches a point where it stops dividing, then the cells die
● The replicative potential of a cell population can be measured as the # of time the cell
population doubles (population doublings)
● Hayflick said a cell could double 40-60 times before apoptosis
● Hayflick limit: an observation that some somatic cells have limited capacity to continue dividing
when sub cultured

WHAT CAUSES REPLICATIVE SENESCENCE?

● Telomeres: the ends of chromosomes that prevent them from sticking together and
accumulating mutations
○ Can function as reflectometers: count cell division cycles as the progressively erode with
every round of replication
○ Once they reach a critical length and become dysfunctional, activating replicative
senescence
○ Telomere length is commonly maintained by the cellular retro transcriptase telomerase,
an RNA dependant DNA polymerase capable of replicating telomeres
● Telomere length decreases with every cell cycle
○ Molecular clock
● Attrition = telomere shortening

SENESCENCE VS. QUIESENSCE

● Senescence is a cell cycle exit or arrest that takes place either in the G one or G two phase of the
cell cycle
● Quiescence, or G zero, is a cell cycle arrest or exit that occurs in the G one phase only
● Unlike a quiescent cell, a senescent cell will not re-enter the cell cycle in response to grow
factors

CHARACTERISTICS OF SENESCENT CELLS

● Replicative senescence (non-post mitotic cells)
● Enlarged cell size + flat morphology
● Prominent Golgi
● Enlarged nuclei and vacuolated cytoplasm
● Enlargement of lysosomes, increased lysosomal β-galactosidase
● Resistance to apoptosis
● Senescence Associated Secretory Phenotype (SASP)
● - pro-inflammatory cytokines, matrix metalloproteinases

● Senescent cells vs. apoptotic cells

○ Senescent cells remain metabolically active and in addition to exiting the cell cycle, if
they were cells that were methodically active, they undergo a serious of in atypic
transformations, both morphological and metabolic, many of which are due to changes
in gene expression due to epigenetic changes
 MANIFESTATION OF THE SENESCENT PHENOTYPE
● Cells acquire the senescent phenotype overtime (accumulation of insults that trigger cellular
senescence)

● Replicative senescence is a characteristic of cells that have proliferation potential

○ Meaning they're methodically active
● Cellular senescence manifests as either loss of cellular proliferation and phenotypical alteration
in dividing cells, or simply phenotypical alterations alone in non dividing cells

FACTORS CAUSING CELLULAR SENESCENCE

SENESCENT CELLS ACCUMULATE WITH AGE

● The effects of cellular senescence can be cell intrinsic, as in the case of direct abrogation
of proliferative capacity or alterations in cell function
● Or cell extrinsic, such as the paracrine induction of senescence in neighboring cells,
mediated by SASP.
● In healthy young individuals and tissues senescent cells are efficiently cleared by the
immune system in a process concomitant with tissue repair
● However, during aging, there's an accumulation of senescent cells, potentially due to
disruptions in the clearance, due to age related malfunction of the immune system
● This accumulation of senescent cells and the associated changes in the cellular micro
environment towards a senescent pro inflammatory type, have been proposed to
contribute to tissue degeneration, malfunction and decline in regenerative capacities

CONTRIBUTION OF CELLULAR SENESCNECE TO AGING - EVIDENCE

1. Injection of senescent cells
2. Interventions that reverse/inhibit senescence
○ Restoration of telomeres
○ Removal (senolytics) or modifications of senescent cells (senomorphics)
○ Caloric restriction

CELLULAR SENESCENCE BENEFITS?

● Function: to prevent the propagation of damaged cells
● A key component of many processes
SUMMARY

SENESCENCE AND THERAPEURTICS