Theories of Biological Aging Dave Morgan Alzheimer Research Laboratory Dept of Pharmacology AGING Successful Typical Unsuccessful Is Aging Universal? Senescence is the age when an organism’s viability is reduced dramatically due to impaired physiology Gradual Senescence Humans, most mammals Negligible Senescence Redwoods, Bristlecone pines, Tortoises, Rockfish, Lobsters Rapid, Obligate Senescence Many insects, Annual plants, Salmon, Some mice Single Celled Organisms Fission produces two daughters of equal seniority Survival Curves Indicate the Effects of Aging on Mortality 100 % surviving at birth (age 0) Early infant mortality Age-independent mortality rate (10-50) Age-dependent mortality rate (60+) 50% = median (~avg) 0% = maximum Lifespan Effects of Slowing Aging Eliminating Disease increases median longevity; rectangularizes the survival curve (1-3). Slowing Aging increases both median and maximum longevity (curve 4). Senescence Occurs Rarely in the Wild In the wild, organisms rarely reach the age of senescence. Age-associated degenerative diseases are recent causes of death Average Longevity has Increased over Time. Maximum Appears Fixed POPULATION Mean Maximum Lifespan Lifespan Wurm (30,000 B.C.) 29 75 Paleolithic (12,000 B.C) 32 110 Mesolithic (8,000 B.C) 31 110 Neolithic (6,000 B.C.) 38 110 Classic Greece (500 B.C.) 35 110 Classic Rome (0 B.C.) 32 110 England (1200 A.D.) 48 110 England (1376) 38 110 United States (1900) 45 110 United States (1950) 70 110 United States (1985) 75 110 Most Infants do not Reach Puberty Infant Mortality was the norm Evolution operates until the age of reproductive success Prehistoric gravesites contain primarily children Longevity Increased Dramatically in the 20th Century Major gain is reduced childhood mortality Likely Causes Sanitation Nutrition Medical Care Leading Causes of Death 1900 1984 RANK Cause of Death Percent Cause of Death Percent Mortality Mortality 1 Pneumonia and 11.8 Heart Disease 37.5 Influenza 2 Tuberculosis 11.3 Cancer 22.2 3 Diarrhea and 8.3 Cerebrovascular 7.6 Enteritis Disease 4 Heart Disease 8.0 Accidents 4.6 5 Cerebrovascular 6.2 C. O. P. D. * 3.4 Disease 6 Nephritis 5.2 Pneumonia and 2.9 Influenza 7 Accidents 4.2 Diabetes 1.8 8 Cancer 3.7 Suicide 1.4 9 Diptheria 2.3 Liver Disease 1.3 10 Meningitis 2.0 Atherosclerosis 1.2 * C.O.P.D. = Chronic Obstructive Pulmonary Disease and Allied Conditions Do Women Outlive Men Because They Are Shorter? Height is inversely related to longevity in many populations with widely divergent overall longevities Women are 8% smaller than men (on average) and live 7.9% longer). The line relating height and longevity is identical for men and women The J Curve. Humanity Dominates Wear and Tear Theories of Aging Extrinsic Causes Stochastic (not determined) Proceeds much like aging in your automobile Biological Clock Theories of Aging Aging is programmed Intrinsic; generated from within Determinant Clocks may exist as a master clock and/or cellular clocks Different species have different maximum longevities even in captive environments Genetics must be the cause of the differences Wear and tear theories claim the genes work by preventing aging Biological clock theories claim the genes directly cause aging (regulate clock rate) Programmed Aging: Limited Cell Proliferation Potential The Hayflick Limit Population Doublings Correlate with Longevity Longer lived species have more population doublings Cells from young individuals have more population doublings Cells from individuals with progerias (accelerated aging syndromes) have fewer population doublings Biological Clock may be Telomeres Caps on the ends of chromosomes get shorter each cell division When telomeres get too short, cells stop dividing Telomerase extends telomeres If telomeres disappeared each generation, the next generation may run out Telomerase permits separation of a mortal somatic cell lineage and an immortal germ line lineage. Multicelled creatures permitted the soma to become disposable Transformed cells activate telomerase Limitations of the Cell Division Hypothesis Tissues (bone marrow) can be serially transplanted to give lifespans far exceeding that of original donor Most of your body mass is post-mitotic cells Telomerase knockouts have normal offspring for several generations Wear and Tear: DNA Mutations Damage to most molecules overcome by replacement (turnover of lipids and proteins). Damage to DNA, the blueprint, if permanent, leads to accumulation of errors. Causes are heat, oxygen, mutagens DNA Repair May Slow Aging Cells have multiple DNA repair systems Accumulated mutations should lead to impaired cell function, even in new cells if damaged DNA is copied Regulation of Inflammation in Transgenic Mice Biological Energy Partitioning As a species, organisms may exchange energy between repair and reproduction. If too little repair, individuals die before they reproduce. Natural selection chooses enough repair to maximize reproductive effort. Theoretically, enough repair leads to negligible senescence (human median longevity of 1000 years). Caenorhabditus Elegans Microscopic nematodes Hermaphroditic, easy to clone About 1000 cells, developmental fate mapped Easy to mutate Several mutations that extend lifespan, also reduce fecundity Radiation extends mouse lifespan Humans may benefit also Survivors of atomic bomb attacks have reduced rates of cancer Hormesis- small amounts of damaging agents toughens the body Tanning, strength training, calluses are examples The Aristotelian Mean “All things in moderation” Longevity maximized by avoidance of excess Longevity may also be maximized by avoidance of abstinence Jeanne Calment. Lived to 123. Died several years ago. Smoked cigars to 110. Drank champagne until she died. Conclusions Aging likely results as an accident. So few organisms reached advanced age there was no evolutionary advantage to avoid aging Pleiotropy. The idea that something could benefit an organism during development, but be detrimental as the organism aged Both biological clock and wear and tear theories have support. Aging, like many diseases is likely to be multifactorial. Theories are not mutually exclusive.
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