physiol lect 20: aging and death

time

2004 (gen biol): 50 min

2005 (physiol): works in 60 min OK

reading:

Ch 49 - last pg! (Solomon 7/e)

brain

Siegel et al 6/e pt 5 Ch 34

senescence

Clark et al 2003

Hayflick, L. 1985 "The cell biology of aging

*shay and wright 2000 "Hayflick, his limit, ..."

*rubin "Promise and problems..." 2002

*Rubin, H "Cell aging..." 1997 Mech Aging Dev 98(1):1-35

Dimri et al 1995 "A biomarker

telomeres

Epel et al 2004 "Accelerated

sharpless and depinho 2004 'Telomeres...'

organismal aging

Kemkes-Grottenthaler 2004 "Parental effects..."

Olshansky and Hayflick 2004 - Scientific American

Rose 1984 "Laboratory evolution..."

Zoller DP 1987 "The physiology of aging..." [ ] should GET A COPY

Ruiz-Torres et al 2003

Melk 2003

*Cristofalo et al 1998

Weinert and Timiras 2003 "Invited review: theories..."

Hornsby, 2002 "Cellular senescence and tissue aging in vivo"

telomeres

baird and kipling 2004

baird et al 2003 'extensive allelic variation...'

kipling 2001 'telomeres, replicative...'

death

read every year: "Brain death & disorders of consciousness"

wijdicks 2000

shewmon 2001

dagi et al 2001

byrne et al 1979 "Brain death -- an opposing viewpoint" [ ] should GET A COPY

mokdad et al 2004 'actual causes...'

mutation

worman and courvalin 'how do mutations...?' 2004

oxidative damage

beckman and ames 1998 - phys reviews - EXCELLENT

genetic

hekimi and guarente 2003

guarente and kenyon 2000 'genetic mechanisms

gems and partridge 2002 'insulin/iof signalling'

caloric restriction

de grey 2005 "the unfortunate influence..."

lin et al 2000 'requirement...'

cohen et al 2004

koubov and guarente 2003 - good review

fontana et al 2004

hormesis

lithgow et al 1995

tatar 1997 'chaperoning...'

semenchenko 2004

outline

death

causes
example #1 cardiac arrest and effect on brain function

death

natural causes
link to aging

aging

correlates

organismal
cellular
molecular

experimental manipulation of lifespan

genetic influence on lifespan

definition of death

clinical diagnosis/definition of brain death
implications with respect to abortion
tie to transplant market

death

how to define causes?

example #1:

50 year old sedentary male with poor nutrition decides to run marathon without training, collapses at mile 13 with cardiac arrest, dies

what caused death?

upstream factors? (french fries, sedentary lifestyle)

precipitating factor (running 13 miles)

downstream...

what happens when heart stops beating?

ischemia - lack of blood flow

leads to

hypoxia - lack of oxygen in a tissue

hypoglycemia - lack of glucose in a tissue

which organ(s) most sensitive to hypoxia and hypoglycemia? A: brain

ATP levels fall
impaired Na/K ATPase function
transmembrane gradients lost
action potential can't fire
neurons can't function

** doesn't mean they're dead

types of ischemia

global ischemia

usu. due to cardiac arrest
also can be due to drowning, CO poisoning, etc

focal ischemia [IMG]

usu. due to occlusion of an artery supplying the brain (e.g., internal blood clot ("thrombus") breaks loose and lodges in brain vasculature)
responsible for most strokes

many other routes to death
what precipitates natural death?

excluding predation, infection, etc. death linked to aging process pretty clearly
death is an event (either dead or alive)
aging is a process

aging

definition = ?

--process-- of intrinsic deterioration
reflected at population level as

(1) p(death) rises

(2) p(producing offspring) falls

correlates of aging

organismal

skin changes: pigmentation, wrinkles

tooth loss

cancer CVD

neurological

neurodegeneration

musculoskeletal

loss of muscle tone

decreased muscle fiber #

brittle bones

cellular

increased senescence markers

discuss senescence and the Hayflick limit

limited number of population doublings for a primary cell

[don't cover telomeres/telomerase]

molecular

oxidative damage of biomolecules:

proteins: carbonyl peroxidation
lipids - peroxidation
nucleic acids - multiple forms of damage

experimental alteration of lifespan

caloric restriction

60-70% of voluntary levels (you may not have much fun...but you'll suffer for a long time...)
from yeast to mammals
obvious evolutionary argument: allows postponing reproduction until a food supply is present

reduced reproductive rate [how examined experimentally??] [ ]

from yeast to mammals
generally, reduced calories result in reduced fecundity, so possibly CR acts through this mechanism

oxidative stress (reactive oxygen species)

possibly cause cumulative molecular damage
genetic evidence: SOD/catalase overexpression in Drosophila results in longer lifespan (no confirmation in transgenic mammalian model yet)

hormesis - 'what won't kill you will make you strong'

thermotolerance - treat a population of flies w/heat stress -- those that survive can cope better in the future

mechanism of lifespan determination has a genetic basis

aging happens at dramatically different rates in different species

birds, bats, mice, humans, yeast lifespans vary substantially
Q: what conclusion can you draw? - aging not simply due to environmental 'wear and tear' but has a genetic component

Drosophila experiment w/selective breeding of older members of population -- increase in mean lifespan of population

genetic influences on aging

hormonal controls

insulin/IGF mutants

C. elegans - live longer
Drosophila - live longer

interestingly, resistant to oxidative stresses

genes involved in oxidative stress responses

all long-lived C. elegans mutants tested thus far are resistant to oxidative stressors

interestingly, mice and rats under caloric restriction are also resistant to oxidative stressors

apoptosis controls

p66shc

induces apoptosis in response to oxidative stress
downstream target of p53
extends mouse lifespan appr. 30%

caloric restriction

mutating SIR2 or reducing NAD⁺ levels (SIR2 substrate) prevents longevity conferred by caloric restriction

in yeast - not exactly close to humans
molecular basis = ?

mammalian SIR2 is induced by cal restriction in rats

blocked by insulin and IGF-1
CR reduces NADH levels (a competitive inhibitor of SIR2?)

what does mammalian SIR2 do?

a deacetylase
deacetylates Ku70 - a DNA repair factor - results in Bax segregation - results in inhibition of stress-induced apoptotic cell death

hypothesis: CR extends lifespan by promoting long-term survival of cells -- this puts apoptosis/senescence at center stage

does any of this make sense?

what is aging?

organ/tissue function declines with age?

hypothesis: less cells in organs with age

as cells are lost from tissue/organ, aging occurs as body is unable to replenish them fully
results in deterioration of tissue/organ function

fits with loss in tissue mass and increase in senescence markers seen in tissues from older individuals

death

"causes" vs. "correlates" - make sure to make the distinction

did tobacco kill the individual? or did lung cancer/emphysema prevent breathing and directly cause asphyxiation? (gun may deliver bullet but the two aren't equivalent)

what about Grandma Sherry? - just died in her sleep? - cause of death = ?

consider:

addictive personality - cigarette addition - lung cancer/emphysema - death

definition of death = ?

M-W: permanent cessation of all vital functions

vital functions = ?

death - a process or an event?

"in-between" areas

coma

persistent vegetative state

minimally conscious

locked in

historical criteria for death

cessation of cardiac activity for a given period of time
cessation of pulmonary activity for a given period of time
cessation of CNS activity for a given period of time

traditional standard: 1 and 2

US currently:

most state laws derived from 1981 President's Commission findings which define death as #3
in CA, 2 doctors must evaluate patient for brain death declaration

Japan currently:

no donor card? you're alive until heart stops beating (brain death diagnosis not legal)
donor card: you can choose between 2 death definitions:

"traditional death"
"brain death"

Q: does having two definitions disturb anyone?

diagnosis (=clinical definition) of brain death

see Wijdicks 2000 and www.ctdn.org and Pape et al 2005

brain injury which is severe can cause change in level of consciousness:

classifications (reality is more of a continuum)

coma

not neurobehaviorally responsive

vegetative state

sleep-week cycles present

minimally conscious

verbalization
response to commands

conscious

communicates
functional use of objects
clear behavioral manifestation of self

note: not a very sophisticated assessment of brain activity - very external

--brain death clinical criteria--

coma

apnea

absence of respiratory drive

tests if medulla functioning

test w/"apneic diffusion oxygenation"

disconnect ventilator - jeopardizes patient!

misdiagnosis possible (locked-in syndrome, hypothermia, drug intoxication) -- but this isn't the main issue

diagnosis is --directly-- coupled to organ transplantation

how does donor (transplant) stuff fit into this?

why interest in brain death? why funny definitions of brain death?

heart starts beating early in development - implications for abortion - defining death defines life

loss of heart function -very- undesirable for transplantation (see p. 466 Shewmon)

heart and lungs can continue to function after CNS stops

easier to get organs for transplantation
transplantation is a significant economic presence
there is a chronic shortage of transplantable organs

ethical problems

'brain death' defined as loss of function - no demonstration that cells themselves no longer viable - a misnomer - it's really what used to be called coma under a new name?

if this comatose state is reversible then even a tentative diagnosis of braindeath is ethically wrong since it

causes efforts to shift toward preserving vital organs instead of focusing on minimizing neurological damage

some observations:

'brain dead' mother carried child to term (107 days of survival) and delivered normal child?
why do embalmers not embalm until patient is really dead?

misc other thoughts/appendix

aging and evolution: a problem

why don't we keep evolving to maximize survival? - the longer organism lives, the more opportunities for reproduction unless reproductive life not equal to lifespan

'trade-off theory'/pleiotropy theory supported most strongly