This presentation gives a detailed analysis of post embryonic developmental changes with special emphasis on metamorphosis and aging.

1. Post embryonic development
Rachel Jacob
ZOO-15-05-10

2. Unit : 6
Post embryonic development

3. Post embryonic developmental changes include
metamorphosis, regeneration and aging .
Metamorphosis is the phenomenon in which larva matures
into the adult through a series of drastic changes.
Regeneration is the creation of new organ after the original
one has been removed from the adult animal.
Ageing is the genetically determined species specific
senescence.

4. Metamorphosis

5. Metamorphosis
is a biological process by
which an animal physically
develops after birth or
hatching, involving a
conspicuous and relatively
abrupt changes in the
animal's body structure
through cell growth and
differentiation.

6. Direct and indirect development
• Direct development: Young are smaller versions of the adult.
E.g., Humans.
• Indirect development: Young (larva) has characters different from the
adult. The larva metamorphoses to produce adult.
E.g., Cecropia moths (Hyalophora cecropia).
• In indirect developers larva are specialized for growth and dispersal.
Adults are specialized for reproduction.

8. Secondary larvae and Primary larvae
• Secondary larvae:
Larvae and adults possess similar
basic body plan.
E.g., Butterfly and Caterpillar
Frog and Tadpole
• Primary larvae:
Body plans of the adult and
larva are drastically distinct.
Eg., Sea urchin larvae and adult

9. Amphibian Metamorphosis
• Amphibians are named for their ability to undergo
metamorphosis.
• Amphibian metamorphosis is associated with
morphological changes which prepare the aquatic
organism for a terrestrial existence.
• In urodeles (salamanders), the changes include:
– Resorption of tail fin
– Destruction of external gills
– Changes in skin structure

10. • In anurans (frogs and toads) changes are more dramatic as every organ
is subject to modification.
• Changes in amphibian metamorphosis are initiated by thyroid
hormones.
• Encounter with thyroid hormones can result in any of the four
responses:
– Growth
– Death
– Re-modeling
– Re-specification

11. • Growth of new structures.
• T3 induces formation of adult
specific organs such as limbs,
eyes and nictitating membranes.
• New neurons proliferate and
differentiate in response to T3 (in
the spinal cord).
• Blocking T3 activity will prevent
neuron development and cause
limb paralysis.

12. • Movement of eyes towards the
front of the head from their
original lateral position.
• Binocular vision develops due to
establishment of ipsilateral
projections.
• In Xenopus new neuronal
pathways are formed due to
formation of new neurons and
not due to re-modelling. This is in
response to thyroid hormones.
• Ephrin –β is induced in the optic
chiasm by the thyroid hormones.

13. II. Cell Death
• Larval specific structures die due to influence of
T3.
• Degeneration of paddle-like tail and oxygen
producing gills.
• First part of tail resorption is caused by apoptosis.
• Remnants of the tail are removed by phagocytosis.
• The enzyme caspase-9 is involved in apoptosis.
• Tadpole’s RBCs die due to phagocytosis.

14. III. Re-modeling
• Larval intestine is made shorter for carnivory.
• Cells of adult intestine are derived from larval
intestine.
• Triggered by digestion of old Extra Cellular Matrix
by metalloproteinase Stromelysin -3 & by
transcription of genes bmp-4 and sonic hedge hog.
• Neurons switch targets. Motor neurons of the
tadpole jaw switch to newly formed adult muscles.
• Neurons innervating tongue muscles form their
first synapses during metamorphosis.
• Lateral line system of the tadpole degenerates and
ears differentiate further.

15. • Shape of the skull changes as new
bones are being made.
• Tadpole skull is neural crest
derived cartilage. Adult skull is
neural crest derived bone.
• Meckel’s cartilage elongates to
double its length.
• Gill and pharyngeal arc cartilages
degenerate.
• Ceratohyal cartilage which anchors
the tongue is re-modeled.

16. IV. Biochemical re-specification
• T-3 induces new proteins to
form in existing cells.
• Tadpoles are ammonotelic.
Adult frogs are ureotelic.
• During metamorphosis, liver
synthesizes enzymes necessary
to create urea from CO2 and
NH3.
• T-3 regulates this change by
inducing transcription factors
that activate urea cycle genes &
suppressing genes for ammonia
synthesis.

18. • This was first demonstrated by
Gundernatsch (1912). Tadpoles
metamorphosed prematurely when fed
with powdered horse thyroid glands.
• Allen (1916) destroyed thyroid glands of
early tadpoles(thyroidectomy).
Metamorphosis was not observed,
instead the tadpoles grew into giant
tadpoles.
• Sequential steps of amphibian
metamorphosis are regulated by
increasing amounts of thyroid hormones.

19. • Threshold model states that different events of
metamorphosis are triggered by different concentrations of
thyroid hormones.
• Low concentrations of thyroid hormones in the early stages
induces limb development.
• High concentration of thyroid hormones induces tail
resorption and intestine re-modeling.

20. • Tissues which express increased level of de-iodinase II are the ones which
respond to thyroid hormones first (and convert T4 to T3).
– E.g., limb rudiments (with high levels of de-iodinase II and TR α
receptor.)
• Thus during the early (pre-metamorphosis), limb rudiments receive
thyroid hormone and use it to start leg growth.

21. • The concentration of T4 increases dramatically and TR β levels
increase, leading to tail resorption.
• TR β is the principal receptor that mediates metamorphic climax. In
this way the tail undergoes resorption only after legs are functional.
• The wisdom of the frog is simple:
“Never get rid of your tail before your legs are functional”
• Some tissues are not responsive to thyroid hormones, e.g., dorsal
retina.

22. • The frog’s brain down regulates
metamorphosis once metamorphic
climax has been reached.
• Thyroid hormones induce a negative
feedback loop, shutting down
pituitary cells which causes thyroid to
secrete them.
• T-3 is found in the anterior pituitary
at metamorphic climax. This inhibits
transcription of Thyrotrophin gene
and thereby initiates a negative
feedback loop.

23. • Cellular response to thyroid
hormones can be regulated by
altering the concentration of
T3 and TR.
• The same stimulus can cause
some tissues to degenerate
while stimulating other cells
and tissues to develop.
• Resorption of tadpole’s tail is
brought about by apoptosis.

24. • The debris leftover is degraded by collagenases
and metalloproteinases and by phagocytosis.
• The response to thyroid hormone is organ
specific.
• Tail tip tissue placed on the trunk degenerates
but eye cup on the tail does not.
• Hence degeneration of the tail is an organ
specific programmed cell death response.

25. • Insect metamorphosis involves the
destruction of larval tissues and
their replacement by an entirely
different population of cells.
• There are 3 major patterns in
insect development.
• Ametabolous development
• Hemimetabolous development
• Holometabolous development

26. • Insect development in which there is no
metamorphosis & immature stages appear
similar to the adults, except that they lack
genitalia.
• It occurs in silverfish, springtails and
firebrats.
• Immediately after they hatch is the pro-
nymphal stage bearing the structures which
enabled it to get out of the egg.
• After this pro-nymphal stage, the insect
grows in size but remains unchanged in
form.

27. • Hemimetabolous development is also known
as incomplete or simple metamorphosis.
• Insects emerge from eggs into nymphs
(larvae) that are similar in shape to the
adults.
• They go through several nymphal stages
(called instars) before they undergo a final
molt into their adult form.
• At the final molt, the insect that emerges out
is winged and sexually mature adult called
Imago.

28. • Complete or holometabolous metamorphosis is
characteristic of beetles, butterflies and moths, flies, and
wasps.
• Their life cycle includes four stages: egg, larva , pupa and
adult.
• The juvenile form hatches out from the egg and is called a
larva.
• The larva undergoes a series of molts, each stage is called an
instar.
• After the final instar, the larva undergoes a metamorphic
molt to become a pupa, which does not feed.
• During pupation adult structures form and replace larval
structures.
• An imaginal molt enables the adult (imago) to shed its pupal
case and emerge.

29. • In holometabolous insects, the transformation
from juvenile into adult occurs within the pupal
cuticle.
• Most of the larval body is systematically
destroyed by programmed cell death, while new
adult organs develop from relatively
undifferentiated nests of imaginal cells.
• Thus within any larva, there are two distinct
populations of cells:
• The larval cells
• The imaginal cells

30. • The cells of the imaginal disc:
Forms cuticular structures of the adult
including wings, legs, antennae, eyes, head,
thorax and genitalia.
• Histoblast nests:
Clusters of imaginal cells that will form in
the adult abdomen.
• Imaginal cells:
Clusters of imaginal cells within each organ
proliferate to form the adult organs as the
larval organs degenerate.

31. • The imaginal cells of the disc can be
seen in the newly hatched larvae as
thickenings of the epidermis.
• Imaginal discs divide rapidly at specific
characteristic times.
• As their cells proliferate, the discs form
a tubular epithelial membrane that folds
in on itself in a compact spiral.
• At metamorphosis, these cells proliferate
and differentiate further as they
elongate.

32. • At the end of the third instar, just before pupation, the leg disc is an
epithelial sac connected by a thin stalk to the larval epidermis.
• On one side of the sac, the epithelium is coiled into a series of
concentric folds: reminiscent of a Danish pastry.
• As pupation begins, the cells at the center of the disc become the
most distal portions of the leg- the claws and the tarsus.

34. • The outer cells become the proximal structures- the
coxa and the adjoining epidermis.
• After differentiating, the cells of the appendages and
epidermis secrete a cuticle appropriate for each.
• A number of adepithelial cells migrate into the disc
early in development.
• During the pupal stage, these cells give rise to muscles
and nerves that serve the leg.

35. • Specification of the general cell fates occurs in the embryo.
• The more specific cell fates are specified in the larval stages.
• Interactions between several genes in the imaginal disc
determine the type of leg structure.
• In the third instar stage leg disc, the center of the disc secretes
the highest concentration of two morphogens: Wingless (Wg)
and Decapentaplegic (Dpp).
• High concentrations of these paracrine factors cause an
expression of distal-less gene.
• Moderate concentrations cause the expression of Dachshund
gene.
• Lower concentration of paracrine factors cause the expression
of Homothorax gene.
• Homothorax gene (purple), dachshund gene (green), Distal-
less (red)

36. • Cells expressing distal-less telescope out to
become most distal structures of the leg-
the claw and distal tarsal segments.
• Those expressing homothorax become the
most proximal structure- the coxa.
• Cells expressing the Dachshund become
the femur and proximal tibia.
• Areas where the transcription factors
overlap produces the Trochanter and distal
tibia.
• In this manner, the gradient of Wg and
Dpp proteins is converted into discrete
domains of gene expression.

37. • The mature leg disc in the third instar stage of Drosophila is unlike the
adult leg.
• It is determined but not yet differentiated.
• Differentiation requires the moulting hormone 20-
hydroxyecdysone(20E).
• The mature leg disc in the third instar of Drosophila does not look like
the adult structure.
• First pulse in the late larval stages initiates formation of the pupa, arrests
cell division in the disc, and initiates the cell shape changes that drive the
eversion of the leg.

38. • The elongation of imaginal discs occurs without cell division and is due to
cell shape changes within the disc epithelium.
• Using fluorescently labeled phalloidin to stain the peripheral
microfilaments of leg disc cells, it was demonstrated that cells are tightly
arranged along the proximal-distal axis.
• Upon providing a hormonal signal, the cells change shape and the leg is
everted- the central cells of the disc becoming the most distal (claw) cells
of the limb.
• The leg structures will differentiate within the pupa, so that by the time
the adult fly ecloses, they are fully formed and functional .

39. • The largest of Drosophila's imaginal discs is that of the wing.
• The wing discs are distinguished from the other imaginal
discs by the expression of the vestigial gene.
• When this gene is expressed in any other imaginal disc, wing
tissue emerges.

40. • Axes of the wing are specified by gene expression patterns.
• In the first instar , expression of the engrailed gene
distinguishes the posterior compartment of the wing from
the anterior compartment.
• The Engrailed transcription factor in the posterior
compartment activates the gene for the BMP-like paracrine
factor Hedgehog .
• Hedgehog functions only when cells have the receptor
(Patched) to receive it.
• Diffusion of Hedgehog activates the gene encoding
Decapentaplegic (Dpp) in a strip of cells at the anterior
region of the wing disc.

41. • Dpp and a co-expressed BMP called Glass-bottom boat
(Gbb) act to establish a gradient of BMP signaling
activity.
• BMPs activates the Mad transcription factor (a Smad
protein).
• Dpp is a short-range paracrine factor. Gbb exhibits a
much longer range of diffusion to create a gradient.
• At high levels, the spalt (sal) and optomotor blind
(omb) genes are activated, whereas at low levels, only
omb is activated.
• Below a particular level of phosphorylated Mad activity
the brinker (brk) gene is no longer inhibited; thus brk
is expressed outside the signaling domain.

42. Dorso-ventral & Proximal-distal axis
• The dorsalventral axis of the wing is formed by
the expression of the apterous gene in the
prospective dorsal cells of the wing disc.
• The vestigial gene remains "on" in the ventral
portion of the wing disc.
• The dorsal portion of the wing synthesizes
transmembrane proteins that prevent the
intermixing of the dorsal and ventral cells.
• At the boundary between the dorsal and ventral
compartments, the Apterous and Vestigial
transcription factors interact to activate the gene
encoding the Wnt paracrine factor Wingless.
• Wingless protein acts as a growth factor to
promote the cell proliferation that extends the
wing.
• Wingless also helps establish the proximal-distal
axis of the wing: high levels of Wingless activate
the Distal-less gene, which specifies the most
distal regions of the wing.
• Vestigial protein :green, Apterous::Red , Yellow: Overlap.

43. Hormonal control of Metamorphosis
• Insect metamorphosis is under hormonal control.
• Metamorphosis of insects is regulated by systemic
hormonal signals, which are controlled by
neurohormones from the brain.
• Insect molting and metamorphosis are controlled by
two effector hormones : the steroid 20-hydroxyecdysone
(20E) and the lipid juvenile hormone (JH ).
• 20Hydroxyecdysone initiates and coordinates each molt
and regulates the changes in gene expression that occur
during metamorphosis.
• Juvenile hormone prevents the ecdysone-induced
changes in gene expression.
• Presence of JH during a molt ensures that the result of
that molt is another larval instar, not a pupa or an adult.
• The molting process is initiated in the brain, where
neurosecretory cells release prothoracicotropic hormone
(PTTH ) .

44. • PTTH is a peptide hormone and it
stimulates the production of ecdysone by
the prothoracic gland by activating the
RTK pathway in those cells .
• Ecdysone is modified in peripheral
tissues to become the active molting
hormone 20E.
• For a larval molt, the first pulse
produces a small rise in the 20E
concentration in the larval hemolymph
(blood) and elicits a change in cellular
commitment in the epidermis.
• A second, larger pulse o f 20E initiates
differention.
• These pulses o f 20E commit and
stimulate the epidermal cells to
synthesize enzymes that digest the old
cuticle and synthesize a new one.
• Juvenile hormone is secreted by the
corpora allata.

45. • The secretory cells of the corpora allata are active during larval molts but inactive
during the metamorphic molt and the imaginal molt.
• As long as JH is present, the 20E-stimulated molts result in a new larval instar.
• In the last larval instar, however, the medial nerve from the brain to the corpora
allata inhibits these glands from producing JH, and there is a simultaneous increase
in the body's ability to degrade existing JH.
• Both these mechanisms cause JH levels to drop below a critical threshold value,
triggering the release of PTTH from the brain.
• PTTH, in turn, stimulates the prothoracic gland to secrete a small amount o f
ecdysone.
• The resulting pulse of 20E, in the absence of high levels of JH, commits the
epidermal cells to pupal development.
• Larva-specific mRNAs are not replaced, and new mRNAs are synthesized whose
protein products inhibit the transcription of the larval messages.
• There are two major pulses of 20E during Drosophila metamorphosis.

46. • The first pulse occurs in the third instar larva and triggers the
initiation of morphogenesis of the leg and wing imaginal discs.
• The larva stops eating and migrates to find a site to begin
pupation.
• The second 20E pulse occurs 10-12 hours later and tells the
"prepupa" to become a pupa.
• The head inverts and the salivary glands degenerate.
• The second pulse transcribes pupa-specific genes and initiates the
molt.
• At the imaginal molt, when 20E acts in the absence of juvenile
hormone, the imaginal discs fully differentiate and the molt gives
rise to an adult.

47. Ecdysone receptors cannot bind to DNA by
themselves.
They first bind to nuclear receptors.
These are Ecdysone Receptors (ECRs).
An ECR protein forms an active molecule by
pairing with an ultra specific (USP) protein.
In the absence of hormone bound ECR, Usp
binds to ecdysone responsive genes and
inhibits their transcription.
Inhibition is converted into activation when
ecdysone receptors bind to Usp.
ECR exists in several isoforms.
Larval tissues and neurons have ECR –B1
isoform.
Imaginal disc and differentiating neurons
have ECR-A.

48. • Insect metamorphosis involves complex interaction
between ligands and receptors.
• The target tissues are not mere passive receptors of
hormones.
• They become responsive to hormones only at
particular times.
• When there is a pulse of 20-E at the middle of the 4th
instar of the tobacco hornworm moth Manduca,
epidermis is able to respond because it expresses
ecdysone receptors.
• Thus timing of metamorphosis in insects can be
controlled by synthesis of receptors in target tissues.

49. • Explain Cecropia metamorphosis using suitable illustrations.
• What do you mean by Biochemical re-specification. How is it important?
• What does the Threshold model of metamorphosis state?
• Elaborate on the responses of cells to thyroid hormones.
• Which are the different stages of metamorphosis in amphibians?
• Which are the different types of develoment in insects?
• What are imaginal discs?
• Explain the establishment of axes in drosophila wing discs.
• How is metamorphosis regulated hormonally?
• Which are the different types of imaginal cells in larvae?

51. Aging can be defined as the time related
deterioration of the physiological functions
necessary for survival and fertility.

53. Gerontology (from Greek: geron, "old man" and-logy, "study
of") is the study of
the social, psychological and biological aspect of aging.
It is distinguished from geriatrics, which is the branch of
medicine that studies the diseases of the elderly.
Characteristics of aging affect all the individuals of a species.
Two major topics in research on aging
1) Life span
2) Senescence
These topics are interrelated.

54. Many evolutionary biologists consider
senescence to be the default state
occuring after the animal has fulfilled the
requirements of natural selection.
After its offspring are born and
raised,the animal can die.eg:Pacific
salmon.
Recent studies indicate that there are
genetic components that regulate rate of
aging. Altering activity of these genes can
alter lifespan of an individual.

55. The maximum lifespan is a characteristic of a species;
It is the maximum number of years a member of species
has been known to survive.
Life expectancy is not a characteristic of species,but of
populations
It is the age at which half the population still survives.

56. Life expectancy of Indians
♂ ♂ - 65.77 years ; ♀ ♀ - 67.95 years

59. Nuclear pyknosis:
With advancing age, the nucleus shrinks
and stains deeply. This is due to the
condensation of the nuclear material.
Aging is accelerated by chromosomal
aberrations and somatic gene mutations
Degeneration of cytoplasmic
organelles

60. Changes in enzymatic proteins
LDH, Ac Pase, Lysosomal enzymes
Catalase, Glutathione peroxidase
Respiratory enzymes, Alkaline
phosphatase, Glucose dehydrogenase

61. Telomeres -specific DNA sequences found only
at the tips of chromosome.
Protect the tips of chromosomes from erosion
and from sticking to one another.
In most normal body cells each cycle of cell
division shortens the telomeres.
Eventually, after many cycles of cell division,
the telomeres can be completely gone and even
some of the functional chromosomal material may
be lost.
Erosion of DNA from the tips of our
chromosomes contributes greatly to aging and
death of cells.
Shortening of telomeres

62. Accumulation of aging pigments
Lipofuscin accumulation
Lipofuscin is the most prevalent and well
studied of age pigments.
It invariably accumulates in most tissues, but
especially in the heart muscle, the skeletal
muscle and the brain.
There is much evidence now that lipofuscin
is a significant contributor to aging and age-
related diseases.

63. Accumulation of free radicals
Free radicals produce oxidative damage in lipids, proteins, or
nucleic acids by consuming an electron to accompany their
unpaired electrons.
Some effects are wrinkled skin, stiff joints and hardened
arteries.
Normal metabolism—for example, aerobic cellular
respiration in mitochondria—produces some free radicals.
Others are present in air pollution, radiation, and certain
foods we eat. Naturally occurring enzymes in peroxisomes and
in the cytosol normally dispose of free radicals.
Accumulation of free radicals

65. Ward Dean M.D.
• Functional decrements in neurons and their associated hormones
lead to aging .
• This theory states that hypothalamus, pituitary and adrenal gland
are the primary regulators and timekeepers of aging.
• Thyroxine is the master rate controlling hormone of the body for
metabolism and protein synthesis.
• In addition, secretion of regulatory pituitary hormones influences
the thyroid.
• The theory also indicate that decrease in protective hormones such
as estrogen, growth hormone and adrenal DHEA
(dehydroepiandrosterone) contribute to aging and that increase in
stress hormones (cortisol) can damage the brain’s memeory center
(hippocampus) and destroy immune cells.

66. Weakened immune system
With age the system's ability to produce necessary
antibodies that fight disease declines.
The immune system may start to attack the body’s
own cells.
This autoimmune response might be caused by
changes in cell-identity markers at the surface of cells
that cause antibodies to attach to and
mark the cell for destruction.

67. Decrease in rate of cell division
The Hayflick Limit Theory of Aging says that the human
cells ability to divide is limited to approximately 50-times,
after which they simply stop dividing (and hence die).
Leonard Hayflick

68.  Glucose, the most abundant sugar in the body, plays a
role in the aging process.
 It is haphazardly added to proteins inside and outside
cells, forming irreversible cross-links between adjacent
protein molecules.
 With advancing age, more cross-links form,
which contributes to the stiffening and loss of elasticity
that occur in aging tissues.

70. The changes occuring in the intercellular spaces and in the lumen of
blood vascular system are examples of extracellular changes.
Dementia
Dementia (taken from Latin, originally meaning "madness", from de-
"without" + ment, the root of mens "mind") is a serious loss of cognitive
ability .
Dementia is common in the geriatric population.
Dementia is a non-specific illness syndrome (i.e., set of symptoms) in
which affected areas of cognition may be memory, attention, language,
and problem solving.
One of the most common forms of dementia is Alzheimer's
disease

71. In Alzheimer’s disease, Amyloid plaques and Tau tangles builds
up and causes the early death of brain cells, which results in a
progressive loss of memory and other brain functions.
Alzheimer’s disease

72. Atherosclerosis is a disease in which
plaque builds up inside arteries.
 Plaque is made up of fat, cholesterol,
calcium, and other substances found in the
blood.
 Over time, plaque hardens and narrows
arteries.
 This limits the flow of oxygen-rich blood
to organs and other parts of body.
 Atherosclerosis can lead to serious
problems, including heart attack, stroke, or
even death.
Atherosclerosis

73. Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue .
This is as opposed to formation of fibrous tissue as a normal constituent of an
organ or tissue.
Eg: Cirrhosis of the liver.
cirrhosis of the liver fibrosis in heart
Fibrosis

74. Parkinson's disease is a degenerative disorder of the central nervous
system.
The motor symptoms of Parkinson's disease result from the death of
dopamine-generating cells in the region of the midbrain.
The most obvious symptoms are movement-related; these include
shaking, rigidity, slowness of movement and difficulty with walking
and gait.
Dementia commonly occur in the advanced stages of the disease.
Other symptoms include sensory, sleep and emotional problems.
PD is more common in the elderly-after the age of 50.
Parkinson's disease

77. Changes in collagen
There is an increase in the amount of collagen proteins deposition in the
intercellular spaces. This influences the permeability of cell membranes,
affects the speed of diffusion of substances in and out and significantly
influences the process of aging.

78. Wrinkles are a by-product of the aging process.
With age, skin cells divide more slowly, and the inner layer, called the dermis,
begins to thin.
The network of elastin (the protein which causes skin to stretch) and collagen
fibers (the major structural proteins in the skin), which support the outer layer,
loosen and unravel, causing depressions on the surface.
With aging, skin also loses its elasticity, is less able to retain moisture, oil-secreting
glands are less efficient and the skin is slower to heal.
All of these contribute to the development of wrinkles.
Aging and Wrinkles

80. Oxidative damage
Aging is a by-product of normal metabolism;
 About 2- 3% of the oxygen atoms taken up by the mitochondria are
reduced to reactive oxygen species (ROS).
 [Reactive oxygen species (ROS) are chemically reactive molecules
containing oxygen ]
These ROS include the superoxide ion, the hydroxyl radical, and
hydrogen peroxide.
 ROS can oxidize and damage cell membranes, proteins, and nucleic
acids.
Evidence for this theory includes the observation that Drosophila that
overexpress enzymes that destroy ROS
(catalase and superoxide dismutase) live 30 -40% longer than do controls .

81. Moreover, flies with mutations in the methuselah gene
live 35% longer than wild-type flies.
The methusaleh mutants have enhanced resistance to
paraquat, a poison that works by generating ROS within
cells
These findings not only suggest that aging is under
genetic control, but also provide evidence for the role of
ROS in the aging process.
In C. elegans, too, individuals with mutations that
increase the synthesis of ROS-degrading enzymes live
much longer than wild-type nematodes .

82. Mitochondrial genome damage
It is thought that mutations in mitochondria could
(1) lead to defects in energy production,
(2) lead to the production of ROS by faulty electron transport,
(3) induce apoptosis.
A recent report shows that there are "hot spots" for age-related mutations
in the mitochondrial genome,
Mitochondria with these mutations have a higher replication frequency
than wild-type mitochondria.
Thus, the mutants are able to outcompete the wild-type mitochondria
and eventually dominate the cell and its progeny.
Moreover, the mutations may not only allow more ROS to be made, but
may make the mitochondrial DNA more susceptible to ROS-mediated
damage.

83. General wear-and-tear and genetic instability
"Wear-and-tear" theories of aging are among the oldest hypotheses.
Wear and tear theory of aging was first introduced by Dr. August
Weismann, a German biologist, in 1882.
As one gets older, small traumas to the body build up.
Point mutations increase in number, and the efficiencies of the
enzymes encoded by our genes decrease.
If a mutation occured in a part of the protein synthetic apparatus, the cell
would make a large percentage of faulty proteins .
If mutations arose in the DNA-synthesizing enzymes, the rate of
mutations would be expected to increase markedly, .
Likewise, DNA repair may be important in preventing senescence, and
species whose members' cells have more efficient DNA repair
enzymes live longer.
Genetic defects in DNA repair enzymes can produce premature aging
syndromes in humans.

86. Progeria is a disease characterized by normal development
in the first year of life followed by rapid aging.
It is caused by a genetic defect in which telomeres are considerably shorter
than normal.
Symptoms include dry and wrinkled skin, total baldness, and birdlike facial
features.
Death usually occurs around age 13.
Progeria [Hutchinson-Gilford syndrome ]

87. Werner syndrome is a rare, inherited disease that causes a
rapid acceleration of aging, usually while the person is only in
his or her twenties.
It is characterized by wrinkling of the skin, graying of the
hair and baldness, cataracts, muscular atrophy, and a tendency
to develop diabetes mellitus, cancer, and cardiovascular disease.
Most afflicted individuals die before age 50.
Werner syndrome

89. In C. elegans, there appear to be at least two genetic pathways that affect aging.
The first pathway involves the decision to remain a larva or to continue growth.
After hatching, the C. elegans larva proceeds through four instar stages, after
which it can become an adult.
Or (if the nematodes are overcrowded or if there is insufficient food) can enter a
nonfeeding, metabolically dormant dauer stage.
It can remain a dauer larva for up to 6 months, rather than becoming an adult
that lives only a few weeks.

90. In the dauer stage, adult development is suppressed, and
extra defenses against ROS are synthesized.
If some of the genes involved in this pathway are mutated,
adult development is allowed, but the ROS defenses are still
made.
The resulting adults live twice to four times as long as
wild-type adults
The pathway that regulates dauer formation & longevity is
the insulin signalling pathway

91. The second pathway involves the gonads.
Germ cells appear to inhibit longevity,
When these cells are removed ,C.elegans live longer.
Germ line stem cells produce a substance that blocks the
effects of a longevity- inducing hormones.

92. The insulin signalling pathway also regulates lifespan in
Drosophila.
Flies with loss-of-function mutations of insulin receptor gene live
nearly 85% longer than wild type.
The insulin signalling pathway also regulates lifespan in mammals.
1] mice with loss-of-function mutations of insulin signalling
pathway live longer than wild type.
2]dog breeds with low levels of insulin-like growth factor[IGF1]
live longer than those breeds with higher levels of this factor.
3]mice lacking 1 copy of IGF1 receptor gene live 25% longer than
wild type.

93. As human life expectancy increases due
to our increased ability to prevent and
cure
disease, we are still left with a general
aging syndrome that is characteristic of
our species.
However our knowledge of regeneration
is being put to use by medicine,and we
may soon be able to ameliorate some of
the symptoms of aging.

94. Questions
• Distinguish between lifespan and life expectancy.
• List the cellular and extracellular changes associated with aging.
• How is oxidative damage responsible for aging.
• Explain the telomerase theory of aging.
• Explain the Wear and Tear Theory of aging.
• What is the influence that hormones exert on the aging process?
• Write on premature aging syndromes.
• What is Hayflick limit?
• How does insulin signalling pathway relate to aging?
• Write on genetically conserved aging patterns with emphasis on
C.elegans.