The Science of Ageing Fergus Doubal 12 th December 2006 Concepts Impact on the organism Demographic shifts in populations

The Science of Ageing Aging v ageing Why is it important/interesting to you? Why can I talk about it? Relative

Hill 1915

Questions Do we age (and does everything)? Why do we age? How do we age?

Sources Wellcome Trust booklet on Ageing Cell 2005 – Vol 120 Online lectures from Dr David Gems – University College London The odd paper

Do we age? Ageing – progressive loss of function with dec fetility and inc mortality with inc age Senescence – the deleterious effects of ageing Think of yourself Think of others Best way of deciding if species age is by determining if the age specific mortality increases

Graphs showing age specific death rates Age Log death rate Death rate For humans our chances of dying from ageing related processes doubles every eight years

What is happening to us? Demographics – change in life expectancy from decrease in infant deaths Speak about external mortality (as it decreases maximum lifespan increases) Speak about the evolutionary unique position we are in The very old ie above 95 are not dying at an increased rate (interesting and confusing)

The numbers game 2000 – 600 million >60y 2025 – 1.2 billion >60y 2050 – 2 billion >60y In dev countries >85y is the fastest growing section of society Women outlive men almost in all societies WHO figures

Do we age? Yes

Why do we age? Conversely why are we here in the first place? Are we here purely to pass on our genes – therefore women become disposable after the menopause and men become more useless the older they get Rather disappointingly there have been over 300 theories of ageing published

Evolutionary theory 1 Senescence programmed to get rid of old useless individuals (limiting pop size and accelerating the turnover inc natural sel) But this does not actually happen – ageing in the natural world does not kill animals as extrinsic mortality is too high So animals do not live long enough to grow old and natural selection is not able to effect ageing

Evolutionary theory 1 For the greater good of the species old individuals should die But natural selection acts at the level of the individual not the species Therefore even though it may seem an overall good idea try telling that to the ant on the street (and any pro-ageing gene would be disadvantageous to the holder)

Evolutionary Theory 3 - “Mutation accumulation” Gradual accumulation of late acting alleles that have not been selected out as the natural selectin pressures are low at advanced years This gradual accumulation subtly affects the species and thus ageing occurs

Evolutionary Theory 3 – “Antagonistic Pleiotropy” We age because genes have two effects. One early good effect and one late bad effect. Eg Testosterone – psych hospital study Contribution to fitness is composite of both the size of the effect and the prob of surviving to benefit Life history trade off

Evolutionary theory 4 – “Disposable soma” Each organism has a finite amount of metabolism It needs to pass on its genes in its lifetime Needs to allocate its energy between itself (soma) and its germ line Eg if it take on average 3 years to find a partner then the organism needs to survive for at least 4 years.

Disposable soma continued Take mice. 10% survive the first year therefore they need to concentrate on finding a mate in the first year. The mouse gives energy to reproduction and passing on its germ line rather than to looking after its own body As it does not look after its DNA it becomes damaged and ages after about 2 years but it does not matter because it is dead by then anyway. Intrinsic mortality is linked to extrinstic morality eg bats

Why do we age? Because after having diverted our energy into producing offspring our bodies neglect to look after their own DNA which leads to a general loss of function

How do we age? Very complex Likely to be due to many genes and downstream genes acting at various timepoints. I will start at the molecular level and then work up to the cellular and then mammalian level finishing off with “I do not really know but it is probably due to insulin and oxidative stress somehow”