Post embryonic development

Rachel Jacob

ZOO-15-05-10

Unit : 6

Post embryonic development

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.

Metamorphosis

Metamorphosis

i s a b i o l o g i c a l p r o c e s s b y w h i c h a n a n i m a l p h y s i c a l l y

d e v e l o p s a f t e r b i r t h o r h a t c h i n g , i n v o l v i n g a

c o n s p i c u o u s a n d r e l a t i v e l y a b r u p t c h a n g e s i n t h e

a n i m a l ' s b o d y s t r u c t u r e t h r o u g h c e l l g r o w t h a n d

d i f f e r e n t i a t i o n .

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.

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

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

• 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

• 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.

• 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.

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.

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.

• 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.

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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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

• 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.

• 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.

• 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.

• 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

• 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.

• 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.

• 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.

• 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.

• 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)

• 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.

• 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.

• 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 .

• 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.

• 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.

• 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.

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.

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 ) .

• 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.

• 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.

• 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.

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.

• 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.

• 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?

Aging can be defined as the time related

deterioration of the physiological functions

necessary for survival and fertility.

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.

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.

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.

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

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

Changes in enzymatic proteins

LDH, Ac Pase, Lysosomal enzymes

Catalase, Glutathione peroxidase

Respiratory enzymes, Alkaline

phosphatase, Glucose dehydrogenase

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

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.

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

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.

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.

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

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.

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

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

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

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

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

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.

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

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 .

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 .

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.

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.

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 ]

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

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.

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

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.

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.

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.

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.