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 -=-= 1. 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 2. reduced reproductive rate [how examined experimentally??] [ ] - from yeast to mammals - generally, reduced calories result in reduced fecundity, so possibly CR acts through this mechanism 3. 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) 4. 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 ---- 1. hormonal controls - insulin/IGF mutants - C. elegans - live longer - Drosophila - live longer - interestingly, resistant to oxidative stresses 2. 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 3. 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 ---- 1. cessation of cardiac activity for a given period of time 2. cessation of pulmonary activity for a given period of time 3. 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: 1. "traditional death" 2. "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) 1. coma - not neurobehaviorally responsive 2. vegetative state - sleep-week cycles present 3. minimally conscious - verbalization - response to commands 4. 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