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choose one or the other:

1. discuss the life history of 
fibroblasts in culture, and how aging in culture contributes  to our 
understanding of aging in the organism

2. discuss the changes in the MAP 
kinase pathway which occur in in vitro senescence.

3. and, on the board, 
it says "discuss the role and adaptive significance of caloric 
restriction to lifespan."

in 1990 Dr C became head of some lab over at 
MCP with a chaired, endowed professorship, but now the cash is missing 
due to the Allegheny fiasco...anyway, Dr Cristafalo is an expert on 
Aging.

the course is called "biochemical basis of disease" but aging 
isn't a disease.
also, most of the information we have is about humans, 
mice, and rats. 

[note: I can not hear him very well :(]

aging has 
become a more popular topic now that the lifespan has increased from 18 
all the way up to about 80 yrs.

Questions: 
-what is aging?
-how do we 
age?
-why do we age?
-how does it work?

1. aging can be described as the 
constellation of deteriorative changes in structure and function which 
results in loss of homeostasis, and an increase in the probability of 
death. 

when we talk about biological aging, it's not time going by, 
it's changes occuring in the cells. 

characteristics of senescence:

throughout the metazoa, the scenario is pretty uniform as to what changes 
occur.
regulation of this is multifactorial and includes both genetic and 
environmental components. Maximum lifespan *potential* is genetically 
determined. Available evidence implies the presence of a highly conserved 
'clock' mechanism which runs at variable, species specific, rates. we 
don't really understand this that well. 

2. right now there is a french 
woman who was 122. she is the oldest person ever. scientists think the 
maximum human age is about 120. 
of importance is the growing role of 
pets as companions for older people. some people tried to get a grant to 
study this. 

how do we age physiologically? at about age 30 for humans, 
we're at our best. great. there is a gradual decline in functional 
phsyiological capacity after that age. the most maximal ability to do 
anything declines after that. the characteristics of aging that are 
important are the ability to maintain homeostasis - ability to return to 
normal levels after a change, like return to resting HR after exercise, 
or whatever. 

so, mortality rate due to various causes increases 
exponentially with age.
so we think that aging causes changes that are 
not well understood, but which produce a kind of cataclysmic 
vulnerability to everything.
if you don't die from the most common cause 
of death, you'll die from the second, third, or fourth, because it's not 
really different, there are always multiple pathologies, it's just which 
one gets worse first.

other characteristics of aging: increased 
mortality, chnages in chemical composition (loss of muscle mass), a broad 
spectrum of progressive deteriorative physiological changes, reduced 
ability to respond adaptively to environemental change (loss of 
homeostasis), and an increased vulnerability to almost every disease.

3. 
why do we age? this is perhaps the most difficult and most important 
point. how can aging, which reduces both survivorship and reproductive 
success and thus evolutionary fitness, result from evolution? How can 
evolution select for this bad thing? well, how do we know it did? B/c of 
the genetic component, presumably it was selected for - it's highly 
conserved DNA. why?
this has puzzled people for a couple of hundred years 
(not the same people the whole time, I guess...)
ideas on aging - 
-wear 
and tear: random damage, which outstrips repair capacity. to repair the 
skin on your face is harder than the skin on your butt which has less sun 
damage, right? the repair capacity is generally species specific with 
respect to how well it works.
-senescence as adaptation: somehow, 
evolution selected for this - if at one time food was restricted, killing 
off old individuals would increase food for younger ones. also would 
prevent vertical interbreeding, increasing variation in gene pool. these 
ideas require a kind of altruism on the part of the old folks, though, to 
give up as it were, so these ideas aren't highly thought of.
-non 
adaptive evolutionary theory: based on the fact that the force of natural 
selection declines with age - late acting genes will not be selected 
against, because the organism usually dies before those genes are 
expressed. in the wild, few species show senescence. Alzheimer's, 
Huntington's, etc were not important when people died at 18! The only 
animals that live a long time are us, pets, and zoo animals. in the wild, 
animals just do not live that long. so evolution optimizes early 
fecundity, and once reproduction occurs, evolution has nothing to say. 
the whole idea of antagonistic pleiotropy - "against multiple effects" - 
evolution selects for features that optimize reproductive success - but 
those features probably have a downside,such that they cause 
deterioration over time. this wasn't a problem before. 

study in 
opossums - island possums and mainland possums- island ones had no 
natural predators,reproduced later in life, and had longer lifespan. 
mainland ones had predators, reproduced earlier, and had shorter lives. 


fig 2 in handout - he's facing the board andI really can't hear him :(

plus there are construction trucks or something outside that are loud.


4. how does this work?
general theories of aging: these are not mutually 
exclusive!

somatic mutation - one of the oldest theories. this suggests 
that somatic cells are continually bombarded by radiation and stuff, and 
that this causes damage, and eventually the damage is incompatible with 
life. this theory came out of studies in radiation biology done during 
and after wwII, and they found that in all spp studied, xrays shortened 
lifespan. but we have no reason to believe that the mechanism by which 
xrays shorten life is the same as the natural mechanism of aging.

errors 
in protein synthesis have been ruled out as a method of aging- idea was 
popular 20 yrs ago- but we have found that older cells and tissues have 
difficulty getting rid of old proteins, and the proteins accumulate.  old 
cells seem engorged with posttranslationally modified proteins. sort of a 
loss of adaptive response here.

neuroendocrine - this theory addresses 
gestation, puberty, menopause, birth, all are regulated by hypothalamic, 
pituitary, adrenal axis wrt timing of the events. this appears to be a 
set of machinery capable of keeping biological time. so may be part of 
aging. many changes occur in this with age. growth hormone decreases with 
age. whether or not this is really a master timekeeper for all aging 
isn't clear, but it is important.

immunological - this theory is based 
on two clear facts - one, immune system capacity declines with age, two, 
the fidelity of the immune system declines with age so autoimmune disease 
increases with age. 

free radicals - popular theory. as you know, these 
are molecules with unpaired electrons. these are generated in normal 
processes, of single electron transfer reactions. in mitochondria, in 
p450 transport systems, etc. mitochondria: O2---P450--->O2* 
(superoxide)---superoxidedismutase-->H2O2---catalase-->H20
or 
H2O2----glutathione peroxidase--->H20
or H2O2-----reduction of 
iron--->OH* --->H2O
women with less iron may make less OH* which is more 
damaging than the peroxide, that may be one reason they live longer.


basis to underscore this whole idea of free radical damage - around the 
turn of the century it wasfound that metabolic rate was inversely 
proportional to size. 
maximum lifespan also seemed to be directly 
proportionate to body size
so maximum lifespan was considered to be 
inversely proportional to metabolic rate. people who exercise worry about 
this...
some things we've learned - free radicals do cause damage, esp 
wrt reperfusion injury say post MI, after clot moves away, influx of 
oxygen, lot of free radical formation, lots of damage occurs. we know 
also that free radicals are important for signalling (?). LIke, NO. 

one 
thing relating to the question is the idea of caloric restriction- it was 
found at cornell that if you place rats on a calorically restricted diet 
- 60% of what they would eat if they chose their food, you increased 
lifespan by 50%.  also, all deterioration was delayed. so a 3 yr old rat 
on restricted diet was like a 1.5 yr old regular rat. originally we 
thought - they eat less, they burn fewer calories, they live longer. but, 
the metabolic rate was the same. they had a dip in metabolic rate 
initially, but then it returned to normal. so the metabolic rate isn't 
the thing here. the adaptive significance- in some spp, it's perceived 
that this is very important for animals to not reproduce in times of 
famine. rats are actually something I couldn't hear, so the idea is the 
mechanisms are selected something if you don't get this this is one of 
the questions - it's adaptively important that animals not have offspring 
during times when no food is available. ok, this is understood. 

take 
vitamin C and E - antioxidants- might help
deprenyl - MAO inhibitor -  
may extend lifespan

is aging characteristic of individual cellsor 
integrated function? individual cells. some old german embryologist found 
this out. he found when an egg was fertilized, it divided into somatic 
and germ lineages, and the germ cells are immortal...but the somatic 
cells get only one shot and then they die. the natural history of somatic 
cells is grow, function, deteriorate, and die.  this was ignored for many 
years until some people here more recently figured this out again...they 
studied human cells in culture - cells went through primary outgrowth 
phase, proliferation phase, and decline phase. normal cells have limited 
lifespan.

cell culture - a method for studying the behavior of animal 
cells, free of systemic variations that might arise in the animal during 
normal homeostasis, and under the stress of the experiment. so we know 
cells age at their own rate, and die of old age, even without input from 
the animal as a whole.

fate of cells in culture--> differentiation, 
death, immortalization, or senescence. 

in vitro senescence - 
is driven 
by replications
is accompanied by physiological changes
is seen in many 
cell types
replicative lifespann of cultures is inversely related to age 
of donor and directly related to species maximum life span. cells from 
sick old people do not live long. weird.

young cells given growth 
factors go into G1, make DNA and divide.
old cells get stuck in 
Gsenescent, but why? Is a signal missing, or is the DNA machinery broken? 
they used an SV-40 virus, which reproduces via cellular machinery, to 
show that the machinery worked. so a signal must be missing. 

they think 
signals aren't getting to nucleus because there is a defect somewhere 
between the surface and the nucleus. there are a lot of signal 
transduction pathways in the cell, and they looked at one - the MAP 
kinase system. 

they gave serum, growth factors to young cells - c-fos 
was expressed
in old cells, it wasn't.
they gave some antioxidants - 
certain ones could turn on c-fos in the old cells.
i think this is what 
he said. now we knwo the pathway called ERK is blunted in senescent 
cells, and the binding of the transcription factor to DNA is also 
defective in old cells. so we're looking at a lesion in cells, 
characteristic of aging...seen  in lymphocytes and in isolated 
someotherkindofcyte. so this may be a common denominator. a signal 
transduction problem.  

intrinsic mutagenesis - really a special case of 
somatic mutation.

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