Blackburn, Elizabeth
<p class="MsoNormal" >BLACKBURN, Elizabeth, Telomeres, UCSF, Dec 4, 2014</p>
<p>
This is Thursday noon: Psychiatry Grand Rounds in LKS 120
at Stanford University; She is a prof at UCSF.</p>
<p>
great intro.... by David... (joke about our immigration policy.)
She is from Tasmania; educ in Australia then to Cambridge.
2009 Nobel. she begins:</p>
<p>
many collabs: Cathy Schaefer at Kaiser Perm.
UCL A Steptoe
UCSF many...</p>
<p>
many influences on diseases and aging:
enviro; life events/ behavior and genetics... inputs to major diseases.</p>
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great image of telomeres: chromos are blue rectangles with orange fluors at their ends...</p>
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protective caps at end of chromosomes.</p>
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end cap.... 2.5 to 3 kilobases in humans...
they are scaffolds for protective proteins... to prevent the DNA from being seen as dna breaks...
susceptible to oxidative damage...</p>
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if TM is too short (= telomere) then issue warning of persistent damage response to telomere uncapping...
this stops cell renewal capability
and impairs mitochondrial func;
pro-inflam tumorigenic factors secretd
can lead to dna instability...</p>
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TMase = telomerase is a ribonuclease...
it has two components: one is the
hTERT core protein...</p>
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after the warning get senescence, mitochondrial malfunction... etc.</p>
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in 80% of common human cancers, they have TMase to restore TM...</p>
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TM length depends on balance of shortening and lengthening... shows a see saw...</p>
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templating component hTER (hTR and hTERC is the RNA templating component...</p>
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hudnreds of difft ways that TMase is regulated...</p>
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how to understand it?</p>
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how do human beings respond if only HALF the TMase...
she first shows a genetic defect that results in half the level of TMase:</p>
<p>
hTERC in built ...
if insufficient. (only half see Vulliamy in 2001)
get early death, immune loss, some cancers, pulm fibrosis etc.
v DM prone...</p>
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how about in the (genetically normal) general population... </p>
<p>
she shows TM length on Y axis vs age to 100 years...
it's a messy scatterplot with a massive cloud but nonetheless with
v mild shortening trend with age.</p>
<p>
so, lessons learned 1b: if you inherit a rare mutation causing half the TMase level then get
early death, cirrhosis, pul fibrosis , DM etc. (the story from genetics)
shows several TMase deficiency syndromes... all lead to short TMs</p>
<p>
we call these TM syndromes...</p>
<p>
she shows a proband at age 10 with dyskeratosis congenita etc
but look at his parents and their grand parents
and you see disorders in TMs
eg in parents see aplastic anemia and seee pul fibrosis in grandparents etc.</p>
<p>
this is autosom dominant.... but there is a change in disease type
from generation to gen. even tho they are all heterozyg.
is the inheritance of teolmeric DNA genetic/ epigenetic or something else:</p>
<p>
Telomeric DNA is neither fish nor fowl... similar to epigenetic... somewhat like it</p>
<p>
so, it does happen in these rare genetic cases
(that there is a lamarkian type inher) but does it matter
in pop at large?...</p>
<p>
but, in the genl population
see Health ABC study Njajou in 2009</p>
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the healthspan... correlated longer TM length in WBCs with longevity...</p>
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Honig 2012 WBC TM length...</p>
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WBC TM length some correl with other tissue but not universal...</p>
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in those with the longest TMs half had died...
but in the quaretile with the shortest TMs 3/4 had died after 14 years (in the oldest pts)</p>
<p>
Cathy Schaeffer from KP... studied
100,000 Kaiser enrollees.</p>
<p>
saliva DNA..... she used big robot to process samples...</p>
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relative TM length...</p>
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max survival was abt 75 in this study (and the TM length would track downward to age 75)
BUT the oldest pts were 95 and the length goes up after age 75 in this group.
(many fewer pts in this older group but they were assoc with longer TMs)</p>
<p>
females have longer TMs than males
males = females until about age 50 (saliva DNA)
then males lose TM length.</p>
<p>
note: in Old Order Amish... male = female TM length and longevity...</p>
<p>
Rehkopf 2013...
in Nicoya Blue Zone longer TMs than in the general Costa Rica population...</p>
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genetics</p>
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lesson 2: common snps of known TM/TMase components
generally shows biased frequecies in centenarians... (ie longer TMs)</p>
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Kaiser study: DNA sample in 2009...
they asked a simple question from these data:</p>
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who died as of 2012 2500 (of the 100,000) had died by 2012...
did shortened TM in 2009 predict death by 2012?... yes!</p>
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the effect size was equivalent to a 20 to 30 pack year hx of cigarette smoking....
it DID affect death rate.</p>
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the shortest TMs (ie those in the shortest quartile) had more death
(than those in the longer quartiles) and it
(seemed to be an indep predictor)</p>
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so, in genl populations, TM length predicts survival...</p>
<p>
The Strong Heart Family Study Zhao 2013</p>
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shortest quartile again had double the chance of developing DM within 5 yrs in Amer Indians.
(predicted by TM shortness in WBCs)</p>
<p>
also predicts all cancer incidence and mortality and CVD, dementia, and DM = diabetes.</p>
<p>
Willeit in JAMA 2010 304 69-75
that assoc showed up only in women.</p>
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so, shorter TMs are assoc with common diseases of aging... cancer, CV dis, DM etc.</p>
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so, is this coincidence or causal? the issue of CAUSALITY*</p>
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in general population </p>
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large GWAS studies eg from Kaiser study...</p>
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what genes are assoc with <b>LTL = human leukocyte telomere length</b>..
in GWAS snps see Codd 2013 GWAS meta-analysis</p>
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clearly assoc with risk of CV disease....</p>
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they found 7 snps (and we found 20)</p>
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they found shortening by abt 3 years worth.</p>
<p>
bladder cancer pts (ie those who already have it)
combine with high depression CES-D > 16.... incr risk of mortality was 1.83</p>
<p>
but with life time depression hx gives you 4.88 incr risk.
and if high level of depr scale > 16 => 3X</p>
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this is Jin 2014 Cancer Epidem biomarkers prev</p>
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low depression had 200 months med survival vs 50 months in high depr cancer pts.</p>
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CV disease</p>
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Heart and Soul Study in VA...
similar finding...</p>
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Farzaneh-Far Whooley in 2010...</p>
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the more your TMs fell in lenth the higher the death rate...</p>
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how abt cancers.... not so simple.... a real curveball...</p>
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melanomas...</p>
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if incr TMase TERT expressen then that CAUSES some cancers...
if just 2X too much TMase, the gene causes melanoma, brain, liver, bladder</p>
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so, not good to have 1/2 TMase and also not good to have twice as much...</p>
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so, there seems to be a sweet spot.... this is true in humans...</p>
<p>
brain -related disorders
cases vs controls...
just looking at WBC TM length...</p>
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length of depression in young people assoc with short WBC TMs
but longer TMS poss assoc with Parkinsons. (less clear)</p>
<p>
CAUSALITY part 2....</p>
<p>
slide of Wu Zixu from 2500 years ago ..... emperor of china:
trying to cross a border and his hair went white...
extreme stress... hair goes white....(as in American presidents)</p>
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chronic psych stress leads to heart disease eg...</p>
<p>
Elissa Epel dept of psychiatry in UCSF and Jue Lin in Liz's lab at UCSF.</p>
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caregive mothers (of child) had short TMs that correl wtih years of caring for disabled child..</p>
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shows a dozen studies...</p>
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perceived stress; major depression, childhood trauma, less education...
see eg</p>
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Steptoe 2011
Needham 2013...</p>
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shows up in Kaiser cohort...</p>
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possible mechs... stress hormones: cortisol, epineph, norepi
big diff see epel 2006</p>
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systemic inflam factors</p>
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systemic oxidative stress...</p>
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see David Spiegel in Brit J of Health Psych 2013...</p>
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dysreg of dirunal cortisol might lead to short TMS and leads to immunosenesc and mito dysfunc.
but which steps are rate-limiting?</p>
<p>
but which mechs are really important...</p>
<p>
this is all in adults; how abt kids...
eg Romanian orphanages drury 2012
exposure to vioelnce in shalev 2013...</p>
<p>
parental edu and SES status of family;
living in a high-disorder neighborhood
autonomic adrenocort rreactivity...
alll affect TM length... many refs.</p>
<p>
but do the kids bounce back and correct later?
no.. entringer in 2011.</p>
<p>
but, in genl population length of health span assoc with TM length ...</p>
<p>
intervention studies: can you change the balance of shorening and lengthening to influence rate of TM shortening?
eg exercise, sleep, O3, stress reduc, cut smoking etc.</p>
<p>
so, complex causality: but telomere attrition... somewhat causal...</p>
<p>
summary:
compromised TM maintenance
leads to impair replenishment and func of human cells</p>
<p>
exec by sever chornic stress</p>
<p>
cumulative thru life</p>
<p>
might be a root factor and can interact with etiologie sof common co-morbid disease of aging...
(but not acting along)</p>
<p>
Q epigenetics and imprinting ? unknown... (Q abt passage from one generation to the next via non-genetic mech)</p>
<p>
Q meditation and Yoga....A only small, explor studies; early... we've only studied for 3 months... not long enough...
one study did show + effec tin 6 months.... we are doing studies...</p>
<p>
"I learned to meditate in 6 days and it's really good" she says... espec mini-meditation.</p>
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