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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
ever too old to become young again? Nat Rev Immunol. 2009 Jan;9(1):57-62.
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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:17/30/2019 Maduracion Envejecimiento y Muerte
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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.png7/30/2019 Maduracion Envejecimiento y Muerte
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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.jpg7/30/2019 Maduracion Envejecimiento y Muerte
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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
ever too old to become young again? Nat Rev Immunol. 2009 Jan;9(1):57-62.
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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/7/30/2019 Maduracion Envejecimiento y Muerte
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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/