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Senescence
Senescence (senex = old man): the process
of deterioration that is associated with
aging.
Maximum life span: the maximum number
of years that a member of a species has
been known to survive. The range is
tremendous. Drosophila = 3 months,
humans = 120 years, some turtles and lake
trout = 150 years, some trees = 1000 years
or more.
Survivorship: the percentage of survivors
in a population versus their age. The
variation is great. Only a small percentage
of wild animals enjoy maximum life span
due to predation and disease. Survivorship
is low for humans in underdeveloped
countries, but much higher and steadily
increasing in developed countries.
Jeanne Calment, the oldest confirmed
human, died in 1997 at 122 years of age.
What is the oldest living organism on earth?
Celebrating its 4,645th birthday in
2002, a bristlecone pine in the
White Mountains of California is
the world's oldest-known living
organism.
The tree clings to rocky ground at
11,000 feet in one of the driest
places on Earth. This conifer took
root when the Great Pyramids were
going up in Egypt.
Bristlecone pines owe their
longevity to their unforgiving
environment. Alkaline soil, scant
moisture, desiccating winds,
constant freezing, and six-week
growing season. Insects, fungus,
and rot have little chance under
such harsh conditions.
Sardinia’s mysterious male methuselahs
More men live past 100 on this Italian island, proportionally, than anywhere
else in the world (Science 291:2074, 2001).
In most countries with reliable records, 5 women reach the century mark for
every man. In Sardinia there is no difference between sexes. The area is very
mountainous, isolated, and the population is inbred, thus, there appears to
be a genetic factor that might be isolated.
The T and B cell immunity declines in these individuals, as in all older
people. However, the body’s innate immunity, composed of macrophages, is
‘turned on’ and takes over many functions in these men after the age of 70.
Antonio Todde, 112
oldest known man
Caloric restriction postpones senescence
One of the most reliable ways to prolong life in laboratory animals is to simply
restrict their calories. When rats were maintained on a low calorie diet
throughout life, they were 15% smaller but they lived 50% longer than litter
mates that ate ad libitum (all they wanted).
If restriction of calories is started later in life, it still works, but lifespan is only
extended 20%. Food restricted rats show less evidence of cancer,
atherosclerosis, and autoimmune disease.
Why does restriction of calories
delay senescence? The
underlying mechanisms are
being studied, but are currently
unclear.
Caloric restriction induces
levels of some antioxidant
enzymes.
Oxidative damage hastens senescence
Oxidative phosphorylation: the process of producing energy through
conversion of O2 to H20 and creation of ATP. Although this reaction is
necessary for survival, it also produces hazardous by products.
Reactive oxygen species (ROS): several highly reactive radicals are produced
at potentially damaging levels during oxidative phosphorylation (superoxide
radical, hydroxyl radical, and hydrogen peroxide).
Detoxification enzymes: several enzymes assist in detoxification of ROS:
Antioxidants: natural molecules that reduce oxidative damage from free
radicals. These include glutathione, vitamin C, vitamin E, and b-carotine.
Oxidants damage DNA, lipid, and protein
DNA damage: during aging, oxidants interact with DNA to produce mutations.
These inhibit DNA replication and transcription and can contribute to cancer.
Oxidants often modify protein: this occurs by inducing formation of carbonyl
groups. Carbonyl groups alter or destroy the proteins normal activity. The
carbonyl content of protein increases dramatically in older organisms. Greater
than 40% of all proteins in older individuals are damaged.
Lipid peroxidation: modification of lipids in membranes leads to altered function.
Lipid peroxidation is associated with increased risk of atherosclerosis, and is
negatively associated with long lifespan. Dietary restriction strongly decreases
serum levels of peroxides.
Oxidative damage causes senescence
If oxidant accumulation caused senescence one would predict that:
1. Oxidative damage should increase with aging: most types of oxidative
damage do increase linearly or even exponentially with increasing lifespan.
2. Longer life span should correlate with low oxidant level or high
antioxidants: levels of serum peroxides in lab animals correlate with their
lifespan. Higher levels of SOD and uric acid are associated with increased
lifespan in rodents.
3. Experimental increase of antioxidants should slow down senescence:
injection of old rodents with the antioxidant, PNB, leads to reduced levels of
oxidative damage to the brain. These animals also performed much better in
tasks, such as navigation of a maze.
Senescence of C. elegans is delayed by 4 genes
C. elegans is a small worm that is studied intensively by developmental
biologists. Four genes of this worm are known to postpone senescence.
Clock 1 gene (Clk-1): loss of this gene causes a slowdown of developmental
processes and senescence. Clk-1 encodes a protein needed for coenzyme Q,
an enzyme important for oxidative phosphorylation (Clk-1 mutants have less
coenzyme Q).
Age-1, daf-2, and daf-16: these genes control entry into a dauer stage, which
occurs when the worms lack food or environmental conditions are poor. If the
genes are active, they can increase lifespan 2-fold.
Methusela gene mutations in Drosophila melanogaster can extend the life span
of flies up to 35%. The gene encodes a G protein that influences resistance to
starvation, heat and oxidative damage.
Werner’s syndrome is characterized by premature senescence
Werner’s syndrome: a rare inherited disease that results in premature aging.
Individuals are normal in childhood, but stop growing in their teens. Patients
are more susceptible to cancer, osteoporosis, diabetes, and cataracts., They
usually die in their late 40s.
WRN: the gene responsible for Werner’s syndrome encodes a helicase, an
enzyme that unwinds DNA for replication, DNA repair, or transcription. Both
copies of the gene must be mutated or lost.
One possible cause of
Werner’s syndrome is
improper DNA repair and
rapid accumulation of
mutations. Another
possibility is improper
transcription of genes
that are needed to
maintain vigor or normal
function.
teenage
48 years old
Progeria
Hutchinson Gilford progeria syndrome: causes children to age rapidly, undergo
senescent changes, and to die as young as 12 years old. It is an extremely rare
disease, and there are only 100 known cases worldwide.
It appears to be caused by a dominant mutant gene of unknown function (it is
thought that the gene might suppress the aging process. Difficult to study.
Symptoms: are similar to aging in older persons. These include loss of hair,
thin transparent skin with age spots, osteoporosis, and atherosclerosis.
The etiology is unclear:
Infants with progeria have
shorter telomeres than normal
children, and this might be
important in the pathogenesis
of this syndrome.
The other main theory is that
the gene is involved in
preventing oxidative damage
by free radicals.
Too few cases to allow the
disease to be studied actively.
Telomerase and senescence
Somatic cells of humans show a limited capacity for proliferation in cell
culture, and this corresponds to aging within the organism. Hayflick’s exp.
Phase 1: cells grow rapidly when placed in culture (30-60 pd)
Phase 2: cell growth rate slows after many population doublings
Phase 3: cells stop growing and can never again enter the cell cycle. However,
cells remain viable for extended periods.
The number of population
doublings that occurs before cells
become senescent varies in cells
from different tissues.
Cells from young individuals divide
many more times than cells from
old individuals. This suggests that
all somatic cells are capable of a
limited number of divisions. Thus,
cell senescence may contribute to
organismal senescence.
Telomeres and senescence
One trigger for cell senescence is
shortening of telomeres. Telomeres are
short repeats of DNA (GGGTTA in
humans) that form caps at the ends of
chromosomes to protect the ends from
wearing down.
Each time that a cells divides, it loses
about 100 bp of telomeric DNA.
Telomeres are about 10 kbp long in
embryonic cells. After about 80 cell
divisions, telomeres wear down to 2
kbp, which is thought to be a minimum
length that triggers senescence.
Telomerase: a reverse transcriptase
that restores telomeres. The enzyme is
active in germ cells and stem cells, but
activity is not detected in most somatic
cells. Telomerase is reactivated in
cancer cells or immortal cell lines.
Experimental introduction of
telomerase into aging human cells
prevents senescence and leads to cell
immortality.
If the telomerase gene is knocked out,
mice develop problems after several
generations. Their telomeres become
too short, they lose fertility, and they
are more susceptible to several
diseases.
Mouse telomeres are much longer
than needed.
Why don’t all cells maintain telomerase?
A safeguard against cancer? Humans are long lived and accumulate mutations
due to oxidants and environmental carcinogens. These mutations accumulate
slowly, requiring about 30 cell divisions before they are significant to cause
cancer.
Once a cell is ‘out of control’ (cancer has started), it needs to divide at least 30
times before it can produce a tumor of only 1 cm3. If cell senescence develops
at 60-80 population doublings, it would provide a safeguard that inhibits
cancer. It is hypothesized that many more tumors would arise spontaneously in
humans if telomerase was expressed in all cells. Mice have active telomerase
in somatic cells and mouse cells are highly sensitive to malignant
transformation. Human cells are very resistant to malignant transformation.
Can telomerase be ‘switched off’ in human cancer cells as a universal type of
therapy? It is an attractive idea, but there are problems:
• Some tumors maintain telomere length by poorly understood mechanisms
that do not require telomerase.
• Therapy would need to target every last cell. If it missed one in a million, the
tumor might grow back.
• If telomerase were knocked out in stem cells, there might be problems with
normal tissue regeneration (skin and blood cell renewal).
Cell Death: apoptosis versus necrosis
Cell death occurs in two ways:
Necrosis occurs in response to injury. Cells are
lysed and release their contents. The membranes
break down causing release of organelles , DNA,
and lysosomes to interact with the adjacent cells.
This induces damage and inflammation (heart
attack, bruise).
Apoptosis or programmed cell death is when the
cell commits suicide for the good of the organism.
Most cells have an intrinsic cell death program that
must be constantly suppressed by survival factors
(cytokines and growth factors).
Apoptosis is a genetically controlled event, it
requires energy, and it allows cell death to occur in
a very controlled manner. The nuclei shrinks and
fragments into small pieces. These are easily
phagocytized by macrophages. There is no damage
to adjacent cells and no inflammation.
Apoptosis occurs normally during development
Physiological apoptosis is common during development.
1.
Selective loss of cells between digits allows formation of fingers.
2.
In the immune system, T cells that recognize self antigens undergo
apoptosis.
3.
After pregnancy, the breast cells undergo apoptosis as the breast
tissue undergoes atrophy.
4.
In the vertebrate central nervous system, up to 50% of some types of
neurons undergo apoptosis if they don’t connect with other neurons
and generate survival signals.
Apoptosis can also be triggered by pathological stimuli (treating cells
with cytotoxic drugs causes apoptosis (cancer chemotherapy).
Apoptosis is controlled by a specific signal pathway
C. elegans is a small worm that is a good model for studying apoptosis. It
only has 1090 cells and 131 die in a programmed manner. Mutations in a gene
called Ced-3 alter this process.
The homologs of Ced-3 in humans are called caspases. These are cysteine
proteases that cleave at aspartic acids in proteins. Caspases compose a
family of proteins that sequentially activate one another in a cascade that
induces cell death.
There are 8-9 other downstream caspases that are activated. They amplify the
signal and they digest important cell components to bring about apoptosis
(DNA, structural proteins, membranes).
The 3rd exam has 40 true/false and 10 short answer questions
The most important topics to focus on are included in a Power
Point file on the web. Go to EXAM 3 for the link.
4-17
senescence
pp 770-790
4-19
EXAM #3
pp 326-790
4-22
review for final
4-24
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4-26
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4-29
FINAL EXAM WEEK
All inclusive final