Hayflick limit

The Hayflick limit or Hayflick
phenomenon is the number of times a
normal human cell population will divide
until cell division stops. Empirical evidence
shows that the telomeres associated with
each cell's DNA will get slightly shorter
with each new cell division until they
shorten to a critical length.The concept of the Hayflick limit was
advanced by American anatomist Leonard
Hayflick in 1961,[1] at the Wistar Institute in
Philadelphia, Pennsylvania, USA. Hayflick
demonstrated that a population of normal
human fetal cells in a cell culture will
divide between 40 and 60 times. The
population will then enter a senescence
phase, which refutes the contention by
Nobel laureate Alexis Carrel that normal
cells are immortal. Each mitosis slightly
shortens each of the telomeres on the
DNA of the cells. Telomere shortening in
humans eventually makes cell division
impossible, and this aging of the cellpopulation appears to correlate with the
overall physical aging of the human body.
Australian Nobel laureate Sir Macfarlane
Burnet coined the name "Hayflick limit" in
his book Intrinsic Mutagenesis: A Genetic
Approach to Ageing, published in 1974.

HISTORY

The belief of cell immortality
Prior to Leonard Hayflick's discovery, it
was believed that vertebrate cells had an
unlimited potential to replicate. Alexis
Carrel, a Nobel prize-winning surgeon, had
stated "that all cells explanted in cultureare immortal, and that the lack of
continuous cell replication was due to
ignorance on how best to cultivate the
cells".[3] He supported this hypothesis by
claiming to have cultivated fibroblasts
from chicken hearts and to have kept the
culture growing for 34 years.[4] This
indicated that cells of vertebrates could
continue to divide indefinitely in a culture.
However, other scientists have been
unable to repeat Carrel's result.[3]
Carrel's result is suspected to be due to an
error in experimental procedure. To provide
required nutrients, embryonic stem cells of
chickens may have been re-added to the

Also, it has been theorized that the cells

Carrel used were young enough to contain

pluripotent stem cells, which, if supplied

with a supporting telomerase-activation

nutrient, would have been capable of

staving off replicative senescence, or even

possibly reversing it. Cultures not

containing telomerase-active pluripotentstem cells would have been populated

with telomerase-inactive cells, which

would have been subject to the 50–60

mitosis cycles until apoptosis occurs as

described in Hayflick's findings.

Experiment and discovery

Hayflick first became suspicious of

Carrel's theory while working in a lab at the

Wistar Institute. Hayflick was preparing

normal human cells to be exposed to

extracts of cancer cells when he noticed

the normal cells had stopped proliferating.

At first he thought that he had made a

technical error in preparing the experiment,but later he began to think that the cell

division processes had a counting

mechanism. Working with Paul Moorhead,

a cytogeneticist, he designed an

experiment to test Carrel's theory of cell

division.

The experiment proceeded as follows.

Hayflick and Moorhead mixed equal

numbers of normal human male

fibroblasts that had divided many times

(cells at the 40th population doubling) with

female fibroblasts that had divided only a

few times (cells at the 10th population

doubling). Unmixed cell populations were

kept as controls. When the male controlculture stopped dividing, the mixed culture

was examined and only female cells were

found. This showed that the old male cells

remembered they were old, even when

surrounded by young cells, and that

technical errors or contaminating viruses

were unlikely explanations as to why only

the male cell component had died.[1][3]

The cells had stopped dividing and had

become senescent based purely upon how

many times the cell had divided.

These results disproved the immortality

theory of Carrel and established the

Hayflick limit as a credible biological

theory that, unlike Carrel's experiment, has

been repeated by other scientists.

theory that, unlike Carrel's experiment, has

been repeated by other scientists.theory that, unlike Carrel's experiment, has

been repeated by other scientists.

CELL PHASE:

Hayflick describes three phases in the life

of a cell. At the start of his experiment he

named the primary culture "phase one".

Phase two is defined as the period when

cells are proliferating – Hayflick called it

the time of "luxuriant growth". After

months of doubling, the cells eventually

reach phase three, a phenomenon of

senescence – cell growth diminishes and

then cell division stops altogether

Telomere length:

The average cell will divide between 50-70 times

before cell death. As the cell divides the telomeres on

the end of the chromosome get smaller. The Hayflick

limit is the theory that due to the telomeres shortening

through each division, the telomeres will eventually no

longer be present on the chromosome. This end stage

is known as senescence and proves the concept that

links the deterioration of telomeres and aging.

The Hayflick limit has been found to

correlate with the length of the telomere

region at the end of a strand of DNA.During the process of DNA replication,

small segments of DNA at each end of the

DNA strand (telomeres) are unable to be

copied and are lost after each time DNA is

duplicated.[7] This occurs due to the

uneven nature of DNA replication, where

leading and lagging strands are not

replicated symmetrically.

[8] The telomere

region of DNA does not code for any

protein; it is simply a repeated code on the

end region of linear eukaryotic

chromosomes that is lost. After many

divisions, the telomeres become depleted

and the cell begins apoptosis. This is a

mechanism that prevents replication error

that would cause mutations in DNA. Oncethe telomeres are depleted, due to the cell

dividing many times, it will no longer

divide. This is when the cell has reached

its Hayflick limit.[9][10]

This process does not take place in most

cancer cells due to an enzyme called

telomerase. This enzyme maintains

telomere length, which results in the

telomeres of cancer cells never

shortening. This gives these cells infinite

replicative potential.[11] A proposed

treatment for cancer is the usage of

telomerase inhibitors that would prevent

the restoration of the telomere, allowing

the cell to die like other body cells.[12] On

the other hand, telomerase activators

might repair or extend the telomeres of

healthy cells, thus extending their Hayflick

limit. Telomerase activation might also

lengthen the telomeres of immune system

cells enough to prevent cancerous cells

from developing from cells with very short

telomeres.

ORGANISM AGING:

It has been speculated that the limited

replicative capability of human fibroblasts

in culture may have significance for human

aging, even though the number of

replications observed in culture is fagreater than the number that would be

expected for non-stem cells in vivo during

a normal postnatal lifespan.[13] Although it

had been thought that the replicative

capacity of human cell lines was inversely

correlated with the age of the human

donor from whom the cell lines were

derived, it is now clear that no such

correlation exists.[13]

Comparisons of different species indicate

that cellular replicative capacity correlates

primarily with species body mass, not

species lifespan.[14] Thus it appears that

the limited capacity of cells to replicate inculture may not be directly relevant to

organismal aging.

     #This article taken from Wikipedia