Evolution, Biology and Aging Chapter 2

Werner’s Syndrome and The Curious Case of Benjamin Button

Evolution and Biology Biological Theories of Aging Evolutionary Perspectives on Aging Genetics and Aging

I. Biological Theories of Aging Rate-of-Living Theories Cellular Theories Programmed Cell Death Theories

Rate-of-Living Theories and Research (Programmed Model) Animal variations in size and heart-rates, etc. seem to be roughly associated with life spans – e.g., mice, dogs, humans, tortoises = some sort of metabolic limit? Delaying reproduction in fruit flies leads to longer life, hibernation can lengthen life, etc. Recent work on caloric restriction suggests it may lengthen life, perhaps in similar ways, by slowing metabolism

Cellular Theories of Aging – Programmed Telomere Shortening Body cells can only divide and reproduce a limited number of times – varies by species – called the Hayflick limit, mice = 15, humans = 50, tortoise = 110 Telomeres at end of chromosomes are needed to reproduce successfully, but get shorter each time until gone Telomerase is an enzyme which will allow these to maintain length, but is usually switched off in cells. Cancers turn on the genes regulating telomerase, and thus cells keep replicating Embryonic stem cells also do this, have potential to develop in various ways and over long time – most specialized cells can’t

Chromosomes with Telomeres

Cellular Theories – Oxidation and Free Radicals (Random Theories) Free radicals are molecules produced as part of cell’s metabolic processes, when oxygen combines with cell products Oxygen plays a critical role in metabolism, but free radicals which are produced are bad…Like rust, they damage genes and chromosomes, immune functions, increase susceptibility to disease. Lowered production of free radicals may be pathway through which some of the other factors, like caloric restriction, operate Various foods and chemicals may serve as antioxidants and may somewhat lower free radical production + Cross-linkage theory – glucose and protein stickiness leading to stiffening of cells

Programmed Cell Death Cells at end of their life span limits go through process called “apoptosis” which means programmed death Possible that there is a genetic program that underlies this in some way, and which could explain many of cellular effects Implications of this might be the possibility of reversal of this program in strategic way Key point is that various theories are probably linked together in some ways, each may capture a part of larger mechanism of how aging takes place

II. Evolutionary Perspective on Aging - Outline Darwin’s theory of evolution Some general models of evolutionary influences on adulthood and aging Genetics and aging

Evolution on the Far Side

Darwin’s Theory of Evolution – 3 Principles Population variation in body structure and behavior Method of reliable inheritance – Mendel’s genes Natural selection for fitness among variants – too many offspring, depends on reproductive success

Some General Ideas of Evolutionary Processes and Aging Lifespan = pre-reproductive + reproductive periods vs. post-reproductive period Evolution operates most directly on genes that regulate development til end of reproductive period Post-reproductive period not regulated as much by evolution = many diseases: ALS, some cancers, Huntington’s chorea, Alzheimer’s, that have not been selected against because not expressed earlier on Gene effects can be complex: good early, and then bad later (antagonistic pleiotropy), May be selected for – APO E4 gene linked to Alzheimer’s, but also protects against diarrhea in kids

Average Lifespan over Human History Only in last century has living into post-reproductive period become common Previously, many diseases of late life were usually not expressed since people died early

Implications of Aging in Historical Context Control of infectious diseases of childhood and death in childbirth have made big changes in lifespan since 1900 We thus get to a lot of physical problems – immune system, skeletal system, sensory problems – that ancestors usually didn’t get to at all because they died before they came along! Development is more heavily buffered in earlier part of life span, much more variable with age in later life However, various genes can be expressed at any point in life course

III. Genetics 001 DNA – 20,000 or so genes on 23 pairs of chromosomes in humans Protein coding genes (2-3 %) vs. regulator genes (?%) and non-coding “junk” (no longer active, ?%) Genotypes vs. phenotypes – e.g., recessive gene defects, such as Werner’s Syndrome – only expressed when both parents have defect, parents themselves are carriers only

Studying Genetic Influences Behavior genetics research – proportion of variance (of 100%) in a trait due to genes Twin studies – MZ versus DZ twins Several major European studies involving thousands of twins across lifespan

Werner’s Syndrome – An Inherited Premature Aging Disorder Rare, recessive disorder – need 2 copies to express, on Chromosome pair 8 Begins in adolescence, aging emerges by 30, twice normal rate Major problem is mutation in an enzyme that is supposed to repair DNA in cell – consistent with free radical theory

What is Evidence with Regard to Longevity and Genetics? About 30% of variation in these samples in life expectancy due solely to genes Good functioning (younger biological age) in later life is also partly heritable Blood pressure, pulmonary function, diabetes, bone loss, muscle strength, walking speed – all these functions have substantial heritability

Gene by Environment Interactions (Genes Shape Environmental Effects) APOE gene on Chromosome 19 has 3 variants – e4 is risk (15x) for earlier Alzheimer’s expression, e2 is protective, e3 is neutral This gene affects repair of neuronal damage, e4 variant is bad at this. Carriers do not benefit from environmental factors like exercise, education in preventing Alzheimer’s onset (Gene x Environment interaction) Another Alzheimer’s gene carried on X chromosome, women more susceptible

Epigenetic View of Gotlieb (Environment Shapes Genes) Genes don’t just rule, however, environment influences processes of evolution and heredity Ex., herding cultures in last 6,000 years and lactose-tolerance gene; this gene remains switched on after weaning in these populations because they depended on milk This gene has been selected for in the “switched on” variant in several populations at higher rate, because of environmental life style Shows how evolutionary processes continue today, shaped by culture – in this case, agriculture