Apoptosis & Cell Aging

1) Apoptosis
 Death is part of life and at the cellular level, it's essential for life.

 Apoptosis is so carefully planned out that it is often called

programmed cell death.

 During apoptosis, the cell shrinks and pulls away from its
neighbors. Then, the surface of the cell appears to boil, with
fragments breaking away and escaping like bubbles from a pot of
boiling water.

 The DNA in the nucleus condenses and breaks into regular-sized

fragments, and soon the nucleus itself, followed by the entire cell
disintegrates.

 A cellular cleanup crew rapidly mops up the remains.

 Scientists confirmed the roles of the human genes in apoptosis.

 Mechanisms of Apoptosis
There are 3 different mechanisms by which a cell commits suicide by
apoptosis.

1. Apoptosis triggered by internal signals: the intrinsic or

mitochondrial pathway. Like Bax to destroyed mitochondrial
outer membrane and release of cytochrome C.

2. Apoptosis triggered by external signals: the extrinsic or death

receptor pathway. Triggered by death activators binding to
receptors at the cell surface like lymphotoxin and tumor
necrosing factor (TNF-α).
 3. Triggered by dangerous reactive oxygen species. Reactive
oxygen species (ROS), which can indiscriminately react with many
cellular biomolecules including proteins, lipids, and DNA to
produce a variety of oxidative lesions. These DNA oxidation
products are a direct risk to genome stability.

4. Apoptosis-inducing factor (AIF) is a protein that is normally

located in the intermembrane space of mitochondria. When the
cell receives a signal telling it that it is time to die.
1) is released from the mitochondria (like the release of
cytochrome C in the first pathway) ;
2) migrates into the nucleus; binds to DNA, which
3) triggers the destruction of the DNA and cell death.

2) Aging:
 is the accumulation of changes in an organism or object over time.
Aging manifests at many levels, from single cell to whole animal.

 Normal human somatic cells lose their dividing potential and

become senescent (aging) about 50 to 60 divisions.

 The hallmark of cell aging is the loss of dividing potential in normal

cells during senescence.
 Scientists demonstrated that there is a global a enua on of G1/S
gene expression during cell aging and proposed that such
attenuation may account for the mortality of normal cells.

 Importantly, most of these G1/S genes are controlled by two

transcription factors NF-Y and E2F.

 Cell Aging as a Molecular Level :

1- Damage to vital proteins called histones plays a big role in
cellular aging.
2- Shortening of telomeres, the protective tips of chromosomes,
leads to production of defective histone.
 Human Telomeres
 Telomeres are sequences of DNA repeating of (TTAGGG) on one
strand bound to (AATCCC) on the other strand.

 Telomeric DNA typically ends in a single-strand G-rich overhang of

between 50 and 300 nucleo des at the 3’ end forming a “T-loop”
structure.

 The length of the repeats varies between chromosomes and

between species.

 Each time a cell divides, an average person loses 30 to 200 base

pairs from the ends of that cell’s telomeres.

 Cells normally divide only about 50 to 70 times, with telomeres

getting progressively shorter unless the cells become senescent.

 telomeres do not shorten with age in tissues such as heart muscle

in which cell do not continuously divide.

 Its find in most Eukaryotic organisms, and a few prokaryotes. The

DNA sequences varies slightly between species.

 Chromatin from older cells, which have been through many

divisions, shows clear differences from chromatin from younger
Cells .

 Loss of telomeric DNA during cell proliferation may play a role in

ageing and cancer.

 Since telomeres permit complete replication of eukaryotic

chromosomes and protect their ends from recombination.
 Telomerase “Telomeres terminal transferase”
 It’s an enzyme made of protein and RNAs subunits that elongates
chromosomes by adding (TTAGGG) sequences to the end of
existing chromosomes..

 It is found in the following:

1- Fetal tissue (embryonic tissue).
2- Adult stem cells.
3- Cancer cells.

 Telomerase activity regulated during development and has a very

low, almost undetectable activity in somatic cells.

 When cells divide, the ends of chromosomes slowly erode,

carrying the risk of losing important genetic information.

 After a certain number of cell divisions, telomeres become so

short they send a message that makes the cells stop dividing.
  Telomere activity is controlled by two mechanisms: erosion and
addition.
 Erosion occurs each time a cell divides.
 Addition is determined by the activity of telomerase.

 Each time a cell divides, the protective "caps" at the tip of

chromosomes.

 As telomeres wear down, their DNA undergoes massive changes

in the way it is packaged. These changes likely trigger “ Cell aging."

 Telomere length, telomerase activity and chromosome

rearrangements in human cells should be measured reguarly.

Effects in vivo of common variations in telomere maintenance in

humans?
 people aged 60 years or older with shorter blood cell telomeres
have higher mortality rates.

 Shorter telomeres associate with:

 3.2 fold higher mortality rate from heart disease
 8.5 fold higher mortality rate from infectious disease.

 Poor survival overall from aggregate of all causes