Maduracion Envejecimiento y Muerte

7/30/2019 Maduracion Envejecimiento y Muerte

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Maduracin, envejecimiento

y muerte

Dr. Julio Hilario VargasDepartamento de Fisiologa Humana

Facultad de MedicinaUniversidad Nacional de Trujillo


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Qu es la vida? Un frenes.Qu es la vida? Una ilusin,

una sombra, una ficcin,y el mayor bien es pequeo;que toda la vida es sueo,y los sueos, sueos son

La vida es sueo

Pedro Caldern de la Barca1635


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Juan Ponce de Len

La isla Bimini y la fuente de la juventud


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The proportion of individuals aged60 years or older is projected to increase

Fuente: Organizacion Mundial de la SaludDorshkind K, Montecino-Rodriguez E, Signer RA. The ageing immune system: is it

ever too old to become young again? Nat Rev Immunol. 2009 Jan;9(1):57-62.


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Aging

To become old: to show the effects orcharacteristics of increasing age.

Mean all changes that occur in the body with the

passage of time including the growth,development, and increasing functional efficiency

that occur from childhood to adulthood, as well as

the degenerative changes that occur later in life.

Progressive loss of physiological capacities that

culminates in death


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The process of becoming old: the phase of full

maturity to death characterized by anaccumulation of metabolic products and

decreased probability of reproduction and survival

Is the degeneration that occurs in an organsystem after the age of peak functional efficiency.

It includes a gradual loss of reserve capacities,

reduced ability to repair damage and compensate

for stress, and increased susceptibility to disease.

Senescence


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Principales caractersticas de la

maduracin y envejecimiento delos sistemas


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Decline in physiologicalparameters in aging humans

Dice JF. Cellular and molecular mechanisms of aging. Physiol Rev. 1993 Jan;73(1):149-59


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Senescence of the Organ Systems

Integumentary System

Photograph of child from The 1974 Science Year.1973 Field Enterprises Educational Corporation

File: wordpress.com

Senescence of the integumentary

system often becomes in the late 40s.

The hair turns grayer and thinner as

melanocytes die out, mitosis slows

down, and dead hairs are not replaced.

The atrophy of sebaceous glands

leaves the skin and hair drier.

As epidermal mitosis declines and

collagen is lost from the dermis, the

skin becomes almost paper-thin and

translucent.

Aged skin has fewer blood vessels

than younger skin, and those thatremain are more fragile.

Many older people exhibit rosacea

Thermoregulation is a serious problem

in old age because of the atrophy of

cutaneous blood vessels, sweat

glands, and subcutaneous fat


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Skeletal SystemAfter age 30, osteoblasts become less active than osteoclasts


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Proteomic Profiling of Mitochondrial Enzymes during Skeletal Muscle Aging.

Staunton L, O'Connell K, Ohlendieck K. J Aging Res. 2011 Mar 7;2011:908035.

Overview of themultifactorial

etiology ofsarcopenia


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Muscular System

Credit: Morgan E. Carlson and Irina M. Conboy, UC Berkeley

One of the most noticeablechanges with age is the

replacement of lean body mass

(muscle) with fat.

Aged muscle fibers have fewer

myofibrils.

The sarcomeres are increasingly

disorganized, and musclemitochondria are smaller and have

reduced quantities of oxidative

enzymes.

With reduced circulation, muscle

injuries heal more slowly and with

more scar tissue.

Motor units have fewer muscle

fibers per motor neuron, and more

motor units must be recruited to

perform a given task


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Nervous System

Cerebral Tissue from a Person with Alzheimer Disease

The nervous system reaches its peakdevelopment around age 30.

The average brain weighs 56% less at

age 75 than at age 30.

The cortex is thinner. The remaining

cortical neurons have fewer synapses,

and synaptic transmission is less

efficient.

The degeneration of myelin sheaths

with age also slows down signal

conduction.

Motor coordination, intellectual

function, and short-term memory

decline more than language skills andlong-term memory.

The sympathetic nervous system loses

adrenergic receptors with age and

becomes less sensitive to

norepinephrine


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During aging there is a progressive accumulation

of damaged molecules and impaired energy

metabolism in brain cells

Mattson MP, Chan SL, Duan W. Modification of brain aging and neurodegenerative

disorders by genes, diet, and behavior. Physiol Rev. 2002 Jul;82(3):637-72.


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Sense Organs

Presbyopia: loss of flexibility in the lenses

Cataracts: Cloudiness of the lensesNight vision is impaired as more and more light

is needed to stimulate the retina


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Endocrine System

The endocrine system degenerates less thanany other organ system. The reproductive

hormones drop sharply and growth hormone

and thyroid hormone secretion decline steadily

after adolescence, but other hormones

continue to be secreted at fairly stable levels

even into old age.


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Endocrine System


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Circulatory SystemCardiovascular disease is a

leading cause of death in old

age.

Senescence has multiple

effects on the blood, heart,

arteries, and veins.

Not adapt well to stress on the

hemopoietic system. The

gastric mucosa atrophies, for

example, it produces

less of the intrinsic factor

needed for vitamin B12

absorption. This increases the

risk of pernicious anemia. As

the kidneys age and the

number of nephrons declines,

less erythropoietin is secreted.

Everyone exhibits coronary

atherosclerosis with age.

Like other connective

tissues, the cardiac skeleton

becomes less elastic


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Normal Arterial Blood Pressure at Various Ages*

*Average for healthy individuals

Circulatory System


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The amounts of lymphatic tissue and red bone

marrow decline with age; consequently there are

fewer hemopoietic stem cells, disease-fightingleukocytes, and antigen presenting cells (APCs).

Immune System


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Effects of ageing on lymphocyte production and thedistribution of cells in secondary lymphoid tissues

Dorshkind K, Montecino-Rodriguez E, Signer RA. The ageing immune system: is it



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Respiratory System

Pulmonary ventilation declines steadily after the

20s and is one of several factors in the gradualloss of stamina.

Stamina: The capability of sustaining prolonged stressful effort


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The syndromes that compose chronicobstructive pulmonary disease

COPD in the elderly is

comprised of the

syndromes of

emphysema, small-

airway obstruction or

reversible airways

(asthma), chronic

bronchitis and, to a

lesser extent,

bronchiectasis

COPD: Chronic obstructive pulmonary disease

Expert Rev Resp Med. 2009;3(5):539-548


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Urinary System

The kidneys exhibit a striking degree of atrophywith age.

From ages 25 to 85, the number of nephrons

declines 30% to 40% and up to a third of the

remaining glomeruli become atherosclerotic,bloodless, and nonfunctional.

The kidneys of a 90-year-old are 20% to 40%

smaller than those of a 30-year-old and receiveonly half as much blood.


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Total energy expenditure at different ages

Males are solid lines (SD); females are dotted lines (SD).

Roberts, Susan B., and Irwin Rosenberg. Nutrition and Aging: Changes in the Regulation of Energy MetabolismWith Aging. Physiol Rev86: 651667, 2006


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Mecanismos de envejecimiento
http://www.google.com/imgres?imgurl=http://www.grg.org/images/Progeria.jpg&imgrefurl=http://www.grg.org/breakingnews2003.htm&usg=__miav5F0XIzK71fH5DFZQP5rPJEw=&h=242&w=191&sz=9&hl=en&start=25&itbs=1&tbnid=xjugLlRwcgpBbM:&tbnh=110&tbnw=87&prev=/images%3Fq%3Dprogeria%252Bmechanisms%26start%3D20%26hl%3Den%26sa%3DN%26gbv%3D2%26ndsp%3D20%26tbs%3Disch:1


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Affects one of each 8 millions of newbornsThe two main syndromes, Werners syndrome and

Hutchinson-Gilford.

Werners syndrome generally doesnt appear untilthe second to third decade of life.

Hutchinson-Gilford syndrome is evident within the

first five to ten years of life.

Theories of possible causes: Mutant gene theory,

telomere theory, free radical theory and helicase

theory

Progeria
http://www.google.com/imgres?imgurl=http://www.grg.org/images/Progeria.jpg&imgrefurl=http://www.grg.org/breakingnews2003.htm&usg=__miav5F0XIzK71fH5DFZQP5rPJEw=&h=242&w=191&sz=9&hl=en&start=25&itbs=1&tbnid=xjugLlRwcgpBbM:&tbnh=110&tbnw=87&prev=/images%3Fq%3Dprogeria%252Bmechanisms%26start%3D20%26hl%3Den%26sa%3DN%26gbv%3D2%26ndsp%3D20%26tbs%3Disch:1http://en.wikipedia.org/wiki/File:Hutchinson-Gilford_Progeria_Syndrome.png


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Progeria

From leftto right, are 15, 12, and 26 years old.

Saladins Anatomy and Physiology. The McGrawHill Companies, 2003


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Hutchinson-Gilford progeria syndrome (HGPS) is a childhood

disorder caused by a point mutation in position 1824 of the

Lamin A/C (LMNA) gene, replacing cytosine with thymine,creating an unusable form of the protein Lamin A. Lamin A is

part of the building blocks of the nuclear envelope

CAUSE

Musich PR, Zou Z. Genomic instability and DNA damage responses in progeria arisingfrom defective maturation of prelamin A.Aging (Albany NY). 2009 Jan;1(1):28-37.


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The Molecular Basis of Nuclear Defects in HGPS

Scaffidi P, Gordon L, Misteli T, 2005The Cell Nucleus and Aging: Tantalizing Clues and Hopeful Promises.PLoS Biol3(11):e395.doi:10.1371/journal.pbio.0030395
http://cellbiology.med.unsw.edu.au/units/images/Hutchinson-Gilford_Progeria_Syndrome.jpg


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Envejecimiento replicativo

Normal organ function usually depends on a rate

of cell renewal.

Human cells cultured in the laboratory divide:

Fetus 80 to 90 times and Adult 20 to 30 times.

After reaching their maximum number ofdivisions, cultured cells degenerate and die.

This decline in mitotic potential with age is called

replicative senescence.Why this occurs?: Much of the evidence points to

the telomere, 20 a cap on each end of achromosome.


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Envejecimiento replicativoFactors affecting the telomere length in primary somatic cells from human tissues

Aubert G, Lansdorp PM. Telomeres and Aging. Physiol Rev88: 557579, 2008

WRN: Werner syndrome, RTEL: Regulator of telomere lengthALT: Alternative lengthening of telomeres

ATM: Ataxia telangiectasia mutated kinaseATR: Ataxia telangiectasia and Rad3-related kinase


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Telomere shortening determines the proliferativelifespan of human diploid fibroblasts

Nicole F. Mathon & Alison C. Lloyd. Milestones in cell division : Cell senescence and cancer

Nature Reviews Cancer1, 203-213 (December 2001)


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Estrs oxidativo o radicales libres

Se produce por el desequilibrio entre la

produccin de oxgeno reactivo (radicales libres)

y la capacidad del organismo de neutralizarlos

mediante sistemas de detoxificacin.Coenorhabditis elegans

La protena skn-1

protege a C. elegans

contra el estrs

oxidativo

Hyung An et al. 2005. PNAS


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The ultimate outcome of oxidative stress is a function of 1) oxidantgeneration, 2) antioxidant defenses, and 3) repair of oxidative damage.

Beckman, Kenneth B., and Bruce N. Ames. The Free Radical Theory of AgingMatures. Physiol. Rev. 78: 547 581, 1998.


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Pleiotropa antagnica

Genes que tienen un efecto positivo en etapas

tempranas de la vida pero tienen efecto negativo

en la madurez.

Testosterona

+

+

Fecundidad

Probabilidadde padecercncer deprstata


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CROSS-LINKING

About one-fourth of the bodys protein is collagen.

With age, collagen molecules become cross-

linked by more and more disulfide bridges, thus

making the fibers less soluble and more stiff.

This is thought to be a factor in several of the

most noticeable changes of the aging body,

including stiffening of the joints, lenses, and

arteries.


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Anormalidades de protenas

Not only collagen but also many other proteinsexhibit increasingly abnormal structure in older

tissues and cells.

The changes are not in amino acid sequence therefore not attributable to DNA Mutations but

lie in the way the proteins are folded and other

moieties such as carbohydrates are attached to

them.


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Teora autoinmuneSome of the altered macromolecules described

previously may be recognized as foreign antigens

and stimulate lymphocytes to mount an immune

response against the bodys own tissues.

Autoimmune diseases such as rheumatoid arthritis

do, in fact, become more common in old age.

http://www.niams.nih.gov/Health_Info/Rheumatic_Disease/default.asp


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Molecular basis of ageing

Dorshkind K, Montecino-Rodriguez E, Signer RA. The ageing immune system: is it



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Collado et al.Nature Reviews Cancer6, 472476 (June 2006) | doi:10.1038/nrc1884

Roads to senescence


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The average length of life in a given population,

Life expectancy


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iPSCs: Induced pluripotent stem cells

Liu GH, Barkho BZ, Ruiz S, Diep D, Qu J, Yang SL, Panopoulos AD, Suzuki K, Kurian L, Walsh C, Thompson J,

Boue S, Fung HL, Sancho-Martinez I, Zhang K, Yates J 3rd, Izpisua Belmonte JC. Recapitulation of premature

ageing with iPSCs from Hutchinson-Gilford progeria syndrome. Nature. 2011 Apr 14;472(7342):221-5.
http://www.thelastlecture.com/http://www.thelastlecture.com/


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Death

There is no definable instant of biological death.Some organs function for an hour or more after

the heart stops beating.

Clinical death is defined in terms ofbrain death,accompanied by a lack of reflexes or lack ofspontaneous respiration and heartbeat.

The real issue is to maintain the best possible

quality of life, and when the time comes to die, todo so in comfort and dignity


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http://www.thelastlecture.com/

Carnegie Mellon Professor Randy Pausch

(Oct. 23, 1960 - July 25, 2008) gave his lastlecture at the university Sept. 18, 2007.
http://www.thelastlecture.com/http://www.thelastlecture.com/

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