Maduracin, envejecimiento y muerte

Dr. Julio Hilario Vargas Departamento de Fisiologa Humana Facultad de Medicina Universidad Nacional de Trujillo

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 Barca 1635

Juan Ponce de Len

La isla Bimini y la fuente de la juventud

The proportion of individuals aged 60 years or older is projected to increase

Fuente: Organizacion Mundial de la Salud

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.

Aging
To become old: to show the effects or characteristics 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

Senescence
The process of becoming old: the phase of full maturity to death characterized by an accumulation of metabolic products and decreased probability of reproduction and survival Is the degeneration that occurs in an organ system 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.

Principales caractersticas de la maduracin y envejecimiento de los sistemas

Decline in physiological parameters in aging humans

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

Senescence of the Organ Systems

Integumentary System
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.
File: wordpress.com

Aged skin has fewer blood vessels than younger skin, and those that remain 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 Photograph of child from The 1974 Science Year. 1973 Field Enterprises Educational Corporation

Skeletal System
After age 30, osteoblasts become less active than osteoclasts

Overview of the multifactorial etiology of sarcopenia

Proteomic Profiling of Mitochondrial Enzymes during Skeletal Muscle Aging. Staunton L, O'Connell K, Ohlendieck K. J Aging Res. 2011 Mar 7;2011:908035.

Muscular System
One of the most noticeable changes with age is the replacement of lean body mass (muscle) with fat. Aged muscle fibers have fewer myofibrils. The sarcomeres are increasingly disorganized, and muscle mitochondria 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

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

Nervous System
The nervous system reaches its peak development 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 and long-term memory. The sympathetic nervous system loses adrenergic receptors with age and becomes less sensitive to norepinephrine

Cerebral Tissue from a Person with Alzheimer Disease

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.

Sense Organs
Presbyopia: loss of flexibility in the lenses Cataracts: Cloudiness of the lenses Night vision is impaired as more and more light is needed to stimulate the retina

Endocrine System
The endocrine system degenerates less than any 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.

Endocrine System

Circulatory System
Cardiovascular 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

Circulatory System
Normal Arterial Blood Pressure at Various Ages*

*Average for healthy individuals

Immune System

The amounts of lymphatic tissue and red bone marrow decline with age; consequently there are fewer hemopoietic stem cells, disease-fighting leukocytes, and antigen presenting cells (APCs).

Effects of ageing on lymphocyte production and the distribution 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.

Respiratory System
Pulmonary ventilation declines steadily after the 20s and is one of several factors in the gradual loss of stamina.

Stamina: The capability of sustaining prolonged stressful effort

The syndromes that compose chronic obstructive pulmonary disease

COPD in the elderly is comprised of the syndromes of emphysema, smallairway obstruction or reversible airways (asthma), chronic bronchitis and, to a lesser extent, bronchiectasis

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

COPD: Chronic obstructive pulmonary disease

Urinary System
The kidneys exhibit a striking degree of atrophy with 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 receive only half as much blood.

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 Metabolism With Aging. Physiol Rev 86: 651667, 2006

Mecanismos de envejecimiento

Progeria
Affects one of each 8 millions of newborns The two main syndromes, Werners syndrome and Hutchinson-Gilford. Werners syndrome generally doesnt appear until the 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

From left to right, are 15, 12, and 26 years old.

Saladins Anatomy and Physiology. The McGrawHill Companies, 2003

CAUSE
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

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

The Molecular Basis of Nuclear Defects in HGPS

Scaffidi P, Gordon L, Misteli T, 2005 The Cell Nucleus and Aging: Tantalizing Clues and Hopeful Promises. PLoS Biol 3(11): e395. doi:10.1371/journal.pbio.0030395

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 of divisions, 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 a chromosome.

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

Aubert G, Lansdorp PM. Telomeres and Aging. Physiol Rev 88: 557579, 2008

WRN: Werner syndrome, RTEL: Regulator of telomere length ALT: Alternative lengthening of telomeres ATM: Ataxia telangiectasia mutated kinase ATR: Ataxia telangiectasia and Rad3-related kinase

Telomere shortening determines the proliferative lifespan of human diploid fibroblasts

Nicole F. Mathon & Alison C. Lloyd. Milestones in cell division : Cell senescence and cancer Nature Reviews Cancer 1, 203-213 (December 2001)

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

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

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

Pleiotropa antagnica
Genes que tienen un efecto positivo en etapas tempranas de la vida pero tienen efecto negativo en la madurez. + Testosterona
Fecundidad

Probabilidad de padecer cncer de prstata

CROSS-LINKING
About one-fourth of the bodys protein is collagen. With age, collagen molecules become crosslinked 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.

Anormalidades de protenas
Not only collagen but also many other proteins exhibit 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.

Teora autoinmune
Some 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

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.

Roads to senescence

Collado et al. Nature Reviews Cancer 6, 472476 (June 2006) | doi:10.1038/nrc1884

Life expectancy
The average length of life in a given population,

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.

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 of brain death, accompanied by a lack of reflexes or lack of spontaneous respiration and heartbeat. The real issue is to maintain the best possible quality of life, and when the time comes to die, to do so in comfort and dignity

http://www.thelastlecture.com/ Carnegie Mellon Professor Randy Pausch (Oct. 23, 1960 - July 25, 2008) gave his last lecture at the university Sept. 18, 2007.