Parrot Heartbeat/Cellular Senescence

From: Michael Ragland (
Date: 10/24/04

Date: Sun, 24 Oct 2004 21:49:31 +0000 (UTC)

>>From a Forums Group:

I have read that while certain animals (elephants, turtles, etc) live
much long lives in terms of years as compared to other animals (rodents,
etc), their lifespans are fairly equal in terms of number of heartbeats,
with the smaller animals running on faster metabolisms "using up" their
ultimate "allotment" of heartbeats faster than the larger animals with
slower metabolisms. All of this makes perfect sense to me.

My main question is this: I thought that birds have relatively fast
metabolisms, with rapid heartbeats. If this is true, though, how do
certain types of birds, like the large breeds of parrots and macaws,
often live for well over 50 years? How does their metabolic rate compare
to that of a small mammal, and if it is similar, why do they not follow
the pattern of heart rate being inversely proportional to lifespan?
The only thing I could come up with is that maybe you can only make
comparisons within classification (mammals, birds, reptiles, etc), for
example elephants live longer than dogs which live longer than mice and
macaws live longer than sea gulls which life longer than sparrows, etc
etc. So I guess the second part of my question is if the heart rate
theory is all inclusive in the animal kingdom or if it is relative to
each separate classification.
I'm sorry if this is a dumb question, it's not for a school assignment
or anything, just my own curiosity/confusion.
Join Date: Oct 2004
Location: Indiana,USA
Posts: 13
I think this might be true Examples: shrews live a short life,while the
tortise lives a long life
Join Date: Oct 2004
Location: The Delta Quadrant
Posts: 29
But parrots (Umbrella Cockatoo and African Grey Congo) can live from
80-100 years.

Electrocardiographic Reference Values for Macaws (Ara species) and
Cockatoos (Cacatua species)
Issn: 1082-6742 Journal: Journal of Avian Medicine and Surgery Volume:
15 Issue: 1 Pages: 17-22
Electrocardiograms (ECGs) were recorded from 41 healthy macaws (Ara
species) and 31 healthy cockatoos (Cacatua species). All birds were
anesthetized via face mask with isoflurane anesthesia. Standard bipolar
(I, II, III) and augmented unipolar (aVR, aVL, aVF, V10) leads were
recorded with birds in dorsal recumbency using a direct-writing
oscillograph. Heart rates for macaws and cockatoos ranged from 231 to
571 beats per minute.
Pretty amazing as to how they can maintain that rate for so many years.
Join Date: Jul 2004
Location: Tennessee
Posts: 6
Originally Posted by pi_of_9
Pretty amazing as to how they can maintain that rate for so many years.
I know, that's what confuses me about the whole thing...I haven't done
much reading on ornithology, but bird biomechanics seem like a
fascinating subject.
Join Date: Oct 2003
Posts: 834
It's called Kleiber's Law.
Basically it goes as C * M3/4, where M is mass and C is a constant that
is different for different types of animals. It seems to work for
metabolism, heart rate, and lifespan. Lung surface area and
encephalization quotient follow the same relationship, but all these
things are inter-related, so scaling the same way shouldn't be too
So birds would have a different constant than mammals which would be
different from amphibians.
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Copyright 2002-2004

Comment: Does Kleiber's Law really explain everything? I've read in more
than one place that most animals have an average of one billion to two
billion heartbeats. The average is stated as about a billion. A big
difference between the two, yes! But there seems to be this myth that
all animals have more or less the same number of heartbeats with smaller
animals having a faster metabolism and using up their allotment quicker
and dying much sooner and larger animals such as elephants and tortoises
which have a slower metabolism and heartrate living much longer but when
all is said and done it comes up approximately the same number of
heartbeats. While this may or may not be a loose general rule I have to
wonder if it is true parrots can live 80-100 years old and have heart
rates ranging from 231 to 571 beats per minute (macaws and cockatoos).
Why was there such a wide discrepancy in heartbeat from 231 to 571? If
that kind of discrepancy occurred in a human their heart would explode.
Assuming this study is genuine and not the prank of a weirdo isn't it
possible the isoflurane anesthesia and leads could have contributed to
this wide discrepancy in heartbeat? In other words, what was the cause
of this wide fluctuation in hearbeat? Or is it normal for parrots to
have such wide fluctuations in their heartbeats due to their metabolism?
If that is the case I find it very interesting they can live to be as
old as they apparently can be.

A side question: What is the heartrate of a chimpanzee, bonobo, gorilla,
clive and monkey compared to a human? What animal has the closest
heartrate to that of a human?

Note: This focuses on the cellular aspects of senescence rather than the
evolutionary ones.

Replicative Senescence
By Olivia M. Pereira-Smith and Michael J. Bertram

 We are all aware of how our bodies change as we grow older. Like most
biological processes, the decline in function of organisms over time is
a complex phenomenon. It therefore is not surprising that no two species
or individuals within a species age in exactly the same way.

The variability in aging between species and between individuals is due
to differences in metabolism, environment, and genetic background. This
variability makes it difficult to directly relate studies of aging in
common laboratory animals like mice and fruit flies to human aging.
However, despite this caveat, such animal model systems have provided
valuable insights into various aspects of aging at different levels of
the complex process.
Experiments with humans are not and cannot be as in-depth and
controlled, for ethical and moral reasons. Because of this limitation,
the information provided by studies of human subjects has only begun to
scratch the surface of the underlying mechanisms of human aging.

One way around this constraint has been to study the fundamental
building block of the human body, the cell, grown in the laboratory by a
technique known as cell culture. To make such cultures, human tissue is
treated with enzymes that degrade the proteins surrounding the cell,
allowing them to be released. They are then placed in specialized dishes
containing a growth-promoting solution, the cell culture medium. The
methods used to release the cells as well as the culture medium allow
selection of the growth of a particular cell type and the establishment
of the cell culture. In this way, cells from tissues such as skin,
liver, and bone as well as tumors can be studied in rigorous
experimental procedures that cannot be performed on humans (Freshney,
1986). Many researchers utilize the cell culture model system, and it
has been yielding new insights into the basic molecular processes of
human biology and aging.

Replicative or cellular senescence was observed and proposed as a model
for aging at the cellular level over thirty years ago by Leonard
Hayflick (1965; Hayflick and Moorhead, 1961). He studied human
fibroblastlike cells obtained from lung and skin. Fibroblast cells are
spindle shaped and are important in maintaining the matrix, the material
around all cells, in these tissues. Fibroblast cells produce proteins
such as collagens and fibronectin, which make the matrix. Hayflick found
that when serially cultured, these cells would undergo rounds of
divisions, but as the culture aged, the cells were no longer able to
divide. In conjunction with the loss of division potential, there were
changes in the morphology, the shape and physical appearance, of cells.
The cells enlarged significantly, and more space was observed between
individual cells. This loss of division potential and the simultaneous
change in morphology was termed cellular/replicative senescence.
Hayflick did a number of experiments to demonstrate that the cell
senescence model was not an artifact of putting cells in culture. These
experiments included using culture medium from senescent cells to
demonstrate that the medium could still support the growth of young
cultures. He also cultured old male cells with young female cells and
showed that the culture was eventually composed of only female cells, as
the male cells aged first.

Although cellular senescence was first described using fibroblastlike
cells, all human cell types that can be grown successfully in culture
undergo cellular senescence. These types include melanocytes and
keratinocytes from skin, adrenal cells from the kidney, T cells from the
immune system, and a large number of epithelial-like cells, which come
from tissues such as eye, prostate, and breast (Smith and Pereira-Smith,
1996). The in vitro lifespan of different cell types varies, but the
maximum lifespan observed has always been fewer than 100 population
doublings. It is important to note that this is the number of doublings
it takes for all the cells in the culture to become senescent and thus
render the culture unable to divide. However, senescent cells are
present at all time points during the lifespan of the culture but are a
minor part of the cell population when the culture is young.

The aging of the culture is not dependent on chronological time, but
rather is measured by the number of cell divisions, or population
doublings, the culture has undergone. This fact was shown by a number of
laboratories that made young cells quiescent, or reversibly nondividing,
by removing essential growth factors. The cells stopped dividing at this
time, but when they were allowed to resume growth, they went through the
same number of doublings as cells that had been growing continuously
(Dell'Orco, Mertens, and Kruse, 1974). Also, when cells are frozen in
liquid nitrogen after various numbers of population doublings and then
thawed and cultured, they undergo close to the same number of doublings
as cells maintained unfrozen in culture. Thus, the cells have an
internal counting mechanism that allows them to "remember" the number of
doublings they have undergone and the number after which they must
become senescent.

An attractive current candidate for the counting mechanism is telomere
shortening, in which dna is lost from the ends of chromosomes at each
division (see article by Warner and Hodes, this issue, for details).
However, as discussed below, it is clear that there are a number of
events--some dependent on telomeres and some not--that result in
irreversible growth arrest. The genetic pathways to senescence, and most
likely some of the alternate pathways as well, do not appear to be
dependent on telomerase (the enzyme that maintains telomere length) and
therefore related to telomere shortening.
The fact that senescent cells are not dead or dying cannot be
overemphasized. Senescent cells are actually resistant to programmed
cell death (apoptosis) and in laboratories have been maintained in their
nondividing state for as long as three years. These cells are very much
alive and metabolically active, but they do not divide. This nondividing
state is irreversible by any biological, chemical, or viral agent. At
this stage of terminal nondivision, it has been shown that the gene
expression cells have undergone global changes compared to those of
their younger counterparts. The relationship between the changes in gene
expression and cellular senescence has not been definitively
established, and it is not known whether any or all of the changes cause
senescence or whether senescence results in the changes in gene
expression. Gene expression changes that could potentially induce
senescence include a repression of cell-growth- inducing transcription
factors (Dimri and Campisi, 1994). However, along with this repression
of growth inducers is an activation of the cell cycle inhibitors, p21
and p16, which are more likely the genes that act to induce cell
senescence and in fact are the end products of genetic programs that
lead cells to senescence (Smith and Pereira-Smith, 1996).

Pathways to Senescence

A number of pathways to senescence exist.
Genetically defined pathways. Immortal cells have escaped the cell
senescence pathways and can grow indefinitely in culture. These cells
can be derived from tumors (although not all tumors have totally escaped
senescence), transformed with viruses, or induced with chemical agents.
To elucidate the genetic pathways that lead to senescence, research has
focused on the differences between immortal cells and normal cells.
Early studies showed that fusion of immortal cells with normal cells
resulted in a senescent phenotype, establishing that senescence, or the
normal phenotype, is dominant over cellular immortality (Pereira-Smith
and Smith, 1983).

This finding demonstrates that the immortal phenotype is due to
recessive genetic mutations in the pathway(s) that lead to senescence.
To extend this idea, an immortal cell complementation study was
undertaken whereby cells from different immortal cell lines were fused
with each other. If hybrids from fusion of two different immortal cell
lines had an immortal phenotype, this would indicate that they must have
a lesion in the same senescence gene or gene pathway. If the hybrid
phenotype of the fusion was regaining normal senescence, the immortal
parental call lines must have mutations in different senescence genes or
gene pathways. In this way, more than forty immortal human cell lines
have been tested, and all fall into one of four complementation groups,
A, B, C, or D. These results indicate that there are four genes or gene
pathways that lead to senescence; inactivation of any one of them is a
necessary step toward immortality (Pereira-Smith and Smith, 1988).

Identification of the genes underlying the complementation groups has
been a slow, arduous process and, at this point, one with limited
success. To date, the chromosomes that harbor the senescence genes for
three of the complementation groups have been identified using the
technique of microcell fusion, by which single, individual human
chromosomes have been introduced into cells lines representing the
different complementation groups and the resulting phenotype
ascertained. Chromosomes 1, 4, and 7 have been identified as carrying
cell-senescence-related genes (Ning et al., 1994; Henslek et al., 1994;
Ogata et al., 1993). morf4, the senescence gene on chromosome 4, was
recently cloned (Bertram et al., 1999).
Alternate pathways. Recently, there have been a number of studies in
which cells have been treated with various agents and induced to quit
the cell cycle and enter a senescentlike growth arrest (Young and Smith,
2000). In these studies, some changes known to occur when cells enter
senescence after undergoing replication have been studied and found to
occur. The most consistent is the enlarged morphology reminiscent of a
senescent cell. It is thought that the mechanism of action in these
cases is through production of changes that affect the cell and also
global gene expression. However, more complete characterization of these
growth-arrested cells is needed to confirm how similar to senescent
cells they truly are. Nonetheless, it seems reasonable to assume that,
depending on the signals a cell receives, it can choose to enter
senescent growth arrest and remain viable or die. The cells enter an
arrested state very rapidly, less than a week after treatment,
suggesting that the time-consuming process of telomere shortening is not
always involved.

Correlation of in vitro Cell Senescence to in vivo Aging

The big question is whether cellular senescence does play a role in
human aging and, if so, in what capacity. There are three areas in which
cellular senescence could affect processes in a living organism (in vivo

The first is loss of division potential in tissues like bone, skin,
liver, and gastrointestinal epithelium. In these examples, the questions
are whether, with time, we are running out of cell divisions or whether
the time increased for cell division to occur is compromising these
organisms, leading to loss of function. An example of in vivo senescence
could be the decline in immune function that is observed with aging
(Miller, 1996). There is evidence that this decrease in immune function
is due at least in part to loss of division response of T cells to
antigens such as viruses. Similarly, one of the common problems of
aging, osteoporosis, could well be due to inadequate division of
osteoblasts, the cells that lay down bone (D'Ippolito et al., 1999).
This phenomenon would allow excessive bone resorption by the osteoblast,
resulting in lower bone density. In fact, in culture, osteoblasts from
older people grow less well than those from young individuals. But in
the case of other tissues like skin, the number of population doublings
that cells can achieve in culture would provide enough cells for as much
as 200 years, which is beyond our known lifespan.

Another attractive role for cellular senescence in vivo is as a cancer
control mechanism. Since the cells can only go through a certain number
of divisions as a primary tumor grows, they will enter senescence unless
they escape growth control by one of the four pathways described above.
This state of senescence will keep tumors from growing and thus prevent
the spread of the cancer. There is also evidence that senescence is
sometimes induced in cells that have been damaged, as an alternative to
cell death and damage. In this way, cell senescence is often in response
to the induction of tumors and would thus act as a line of defense
against cancer progression.
Senescent cells may themselves be a disruptive and destructive force in
some instances. Senescent fibroblast cells have been shown to accumulate
with age in skin biopsies (Dimri et al., 1995). For fibroblasts, in
particular, senescence is accompanied by increased expression of
degrading enzymes like collagenase and stromelysin. These enzymes
potentially could be detrimental to the environment outside and around
the cell and thus could affect all the other, nonsenescent cells nearby.
In skin, for example, this could lead to a loss of integrity, resulting
in the wrinkles and loss of elasticity common with aging. Another
possibility is that this change in tissue composition would make tumor
metastasis easier and thus might explain why tumor formation increases
with age.

However, these possibilities are based on more conjecture than fact, and
it remains to be proven that replicative senescence does affect in vivo
aging. Better markers of senescent cells are needed to allow for an
unequivocal demonstration that this is the case. The problem has been
that many of the genes that define senescence are also expressed in
nondividing, quiescent cells. Perhaps the complementation group-related
genes would act as better markers of the true senescent state.

The study of cellular/replicative senescence has clearly advanced the
understanding of basic biology, cell cycle control, and transcriptional
regulation of genes. The fact that telomerase can extend the number of
population doublings that cells can undergo provides a powerful tool for
ex vivo "gene therapy," in which a person's own cells can be genetically
manipulated to compensate for a defect and then returned to the
individual (see Hornsby, this issue, for details). There is clearly a
lot left to be done to demonstrate the role of this phenomenon during in
vivo aging, but as critical genes are identified, they can be analyzed
in animal models and human aging models to better define the impact of
cell aging on the actual human aging process.
Olivia M. Pereira-Smith, Ph.D., is professor, Division of Molecular
Biology and Departments of Medicine and Cell Biology, Baylor College of
Medicine, HuYngton Center on Aging, Houston, Tex. Michael J. Bertram,
Ph.D., is assistant professor, Department of Medicine, Division of
Endocrinology and Metabolism, University of Alabama, Birmingham.

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