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Memory is short, and braine is dry. My Almond-tree (gray haires) doth flourish now, And back, once straight, begins apace to bow. My grinders now are few, my sight doth faile My skin is wrinkled, and my cheeks are pale. No more rejoyce, at musickes pleasant noyse.

Anne Bradstreet (1612-1672) Anne Bradstreet (1612-1672)

EVOLUTION OF SENESCENCE

 Why do we age and die?

 Why do we have a particular suite of age-related diseases?

 Can we delay aging and/or make it more ‘successful’?

 What can evolutionary biology contribute to understanding aging and our aging population?

The Challenges of GLOBAL AGING

•  20th century – saw a global phenomenon of longevity – a triumph and a challenge

•  Average life expectancy at birth- increased by 20 years since 1950 to 66 years

•  Is expected to increase another 10 years by 2050 •  By 2050, the population of older people will exceed that of

children (0-14 yrs) •  Is a social phenomenon without historical precedent •  In 2002, number of persons > 60 years was 605 million •  By 2050, number is expected to reach almost 2 billion

Defining and measuring aging

 SENESCENCE/AGING – deteriorative changes that occur in an individual with increasing age - increase with age in probability that an organism will die from internal reasons, and decrease with age in rate of reproduction  Examples of deteriorative changes: hair loss or greying, slowed reactions times, memory loss, increasing cancer rates and type 2 diabetes rates  Can quantify via age-specific rates of survival and reproduction - is property of populations and species ->  Life-span is not a good measure of aging, as it includes extrinsic mortality risk (eg accidental death) -eliminate these risks and life span would change but senescence rate would not (in short term)  Without aging/senescence, and with physiological peak performance, life expectancy would be about 5000 years

Before After

Examples of age-specific rates of survival and reproduction

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EEK! SENESCENCE REDUCES SURVIVAL AND REPRODUCTION - SO WHY DO WE SENESCE?

FIRST, THE INTENSITY OF NATURAL SELECTION INEVITABLY DECLINES WITH AGE, BECAUSE THERE ARE FEWER OLDER INDIVIDUALS (DUE TO EXTRINSIC MORTALITY), AND LESS OF THEIR REPRDUCTION IS AHEAD OF THEM

…the forces of natural selection weakens with increasing age …. If a genetical disaster… happens late enough in individual life, its consequences may be completely unimportant. Even in such a crude and unqualified form, this dispensation may have a real bearing on the origin of innate deterioration with increasing age. Medawar, 1952

LATE-ONSET MUTATIONS ARE NOT ELIMINATED BY NATURAL SELECTION

EXAMPLE: Huntington’s chorea: disabling disorder of the nervous system caused by a dominant mutation that is not expressed until the age of 35 – 40.

George Sumner Huntington

Another example: Hereditary nonpolyposis colon cancer

•  A heritable genetic disease causing colon cancer

•  The median age of diagnosis is 48, well after the typical reproductive age in humans

Evolutionary hypothesis of aging

•  Aging is not due to unavoidable cellular and tissue damage, but is instead associated with failures to completely repair damage; complete repair should be entirely feasible, in theory

•  Incomplete repair may be due to – Deleterious mutations – Trade-offs between repair and reproduction, or

between other pairs of factors

ANTAGONISTIC PLEIOTROPY HYPOTHESIS

 Senescence occurs because of the pleiotropic effects of genes.

 Selection for alleles which enhance survivorship and/or reproductive rate at early reproductive ages may also lower survivorship and reproductive rates at later ages.

 There is a tradeoff (antagonism) between fitness components early in life and later in life

MUTATION ACCUMULATION HYPOTHESIS

 Senescence occurs because of mutations that have no effect early in life, but deleterious effects late in life; these are nearly neutral and can drift to appreciable frequency, accumulating in genomes over evolutionary time

Early o Late -

Early + Late -

A pleiotropic mutation affects two different life history characteristics->

Benefits of early reproduction may be selected for while selection against reduced lifespan may be minimal

Example of antagonistic pleiotropy

Mature age 3, die by age 16, expected RS 2.419

Mature age 2, die by age 10, expected RS 2.663

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Kirkwood developed the Disposable Soma Theory as a general mechanism for the operation of antagonistic pleiotropy

Organisms face tradeoffs between reproduction and maintenance/repair (soma)

Alleles and physiological mechanisms increasing allocation to reproduction compromise somatic maintenance and repair (eg testosterone & immunity; eg castration can extend life)

Genetic tradeoffs: physiologies that are genetically different (eg genetic change increases fertility but shortens life)

Physiological tradeoffs: tradeoffs within individual depending on conditions (eg have more kids, have shorter life)

"The secret of life is enjoying the passage of time.“ James Taylor

Predictions of evolutionary models of senescence

(1) Patterns of aging have a genetic basis: -artificial selection for late-life reproduction leads to delayed senescence in Drosophila (Rose 1984)-> -lifespan is heritable in humans (30-50%) (2) Higher extrinsic mortality risk should be associated with accelerated senescence, and vice versa (accidental death determines strength of selection on age-specific survival and reproduction) -experimental tests with possums -> (3) Mutations with age-specific effects are common -some evidence but need more (4) Many genes each of small effect are expected to underlie antagonistic pleiotropy effects

EXPERIMENTAL EVIDENCE FOR ANTAGONISTIC PLEIOTROPY - Drosophila artificial selection in the lab

LATE REPRODUCTION

EARLY REPRODUCTION

A natural experiment on the evolution of aging with the Virginia Opossum (Austad 1993)

•  Sources of mortality: – Ecological –  Intrinsic

•  In populations with low ecological mortality, selection may favor delayed senescence (and eliminate deleterious late-acting alleles)

•  Study compared island population (low ecological mortality) to mainland population (high ecological mortality)

Differences in mortality rates

Differences in parental investment

Differences in rates of physiological aging?

Do differences reflect trade-offs between reproduction and repair? If ecological mortality is high, best strategy may be for early reproduction.

Island individuals show evidence of delayed senescence MOLECULAR AND PHYSIOLOGICAL (proximate) MECHANISMS OF AGING

(1) Dietary restriction after adulthood reduces effects of aging & leads to increased lifespan, in lab animals (yeast, worms, Daphnia, Drosophila, mice, primates). Molecular basis of this effect is rapidly being uncovered

(2) Insulin/IGF-1 signalling pathway genes are strongly implicated in aging effects - these genes regulate metabolism and stress responses, affect maintenance functions -> findings falsify one prediction of antagonistic pleiotropy, because aging is largely underlain by one system

BUT WHAT ABOUT TRADE-OFFS AND LIFE-HISTORY THEORY?

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Integrating molecular mechanisms with life-history theory

(1)  Insulin/IGF1 (‘growth’ hormones) pathway appears to strongly regulate tradeoffs between growth, maintenance and reproduction, via adaptive responses in allocation patterns to different environmental signals

-poor environment (eg dietary restriction) - increase maintenance (survival), reduce growth and/or reproduction -good environment - increase growth and/or reproduction, decrease maintenance

(2) In lab, life-span extending mutations have pleiotropic effects that involve substantial costs in terms of other fitness components - fits with presence of trade-offs; in humans, insulin/IGF mutants do poorly & do not show evidence of long lives. However:

Another important form of trade-off: between cancer risk and senescence via cumulative loss of functioning cells

Judy Campisi, UC Berkeley

p53 gene, cancer risk, and aging in mice

p53 alleles in this mouse strain:

+ = wild type - = loss of function m = mutation

Good news! The m allele appears to confer resistance to tumors (6% vs >45%)

Bad News! The m allele appears to have a cost in terms of aging (die off sooner than p53+/+ wild types)

Genetic basis of aging: the APOE example

Apolipoprotein E (APOE) transports cholesterol

Humans have 3 alleles, E2 (0-15%), E3 (50-90%), E4 (5-40%) with different binding affinities to low-density lipoprotein receptor; E4 is ancestral, E3 and E2 arose recently (<200k years ago)

E4 allele confers higher risk of Alzheimer’s disease and cardiovascular disease

Advantage of E3? Delay cognitive and cardiovascular disease? E4 persistence?

The Oxidative-Damage/Free-Radical Hypothesis Of Aging

Oxidative cell damage ↓

Mitochondrial Damage

Oxygen-free radicals release

-DNA Damage -Cross-linking

proteins -Mitochondria

Damage -Form age pigments

Self–perpetuating Cycle of Impaired

Function ↓

Increased Oxygen -free radicals

Be careful not to confuse proximate with ultimate explanations for aging!

Human aging and evolution

Humans have quite-recently evolved a much longer lifespan, based on comparative-phylogenetic studies of primates; the genetic basis of this extension remains to be elucidated and requires studies of positive selection

This longer lifespan (and the alleles underlying it) evolved in ancestral human environments quite different from those today; early-acting beneficial genes in ancestral environments may be irrelevant in modern environments and late-acting effects may not be deleterious

In developed and developing countries, females are reproducing much later in life, which his expected to lead to delayed senescence across generations

There is no physiological or evolutionary reason to think that we cannot ‘break’ the trade-offs that underly senescence and live a very very long time

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The Greek God Zeus granted Tithonus the gift of immortality, but not of perpetual youth, when requested by his wife Eos. Tithonus grew progressively ancient, and begged for death to overcome him

Tennyson’s poem “Tithonus”:

“Man comes and tills the field and lies beneath, And after many a summer dies the swan. Me only cruel immortality Consumes: I wither slowly in thine arms”

Living longer without youthful vitality is not a good idea