BARZILAI Nir Aging in Humans  Jan 30 2012

he is at Albert Einstein Col of Med.

MD, direc of Inst of Aging Research

chaired prof of med and genetics..

Israeli...

nice pix of Albert Einstein as he aged...

Do we humans age at  difft rates? he calls for a vote by the audience:
everybody raises their hands...

he looked at centenarians to see why they are different...

 Aging is the major risk factor for death from ALL chronic diseases...

all diseases go up exponentially with age...

heart disease, cancer, stroke, emphysea, pneumonia,  diabetes, accidents, kidney dis, alzheimers...

Is life span determined by genes or by the environment? he asks the audience...

80% environment and 20% genetics  is the real answer...

(our audience votes  60% genes and 40%  enviro)

for centenarians more like  80% enviro and 20% genes...

***

only 1 person in 10,000 individuals reaches 100 years  (its now 1 in 5000)

they looked at over 540 centenarians  age 95 to 112;...
must be indep living at age 95...

*  there is a remarkable fam history of exceptional longevity in parents, sibs, and offspring of centenarians...

are there  inherited protective factors than can assure human's longevity or perfect genome...
(they got the X-Prize)... perfect sequence...

evidence suggests  that Answer is NO... they still have a lot of bad snps...

pic  4 kids of 2 parents... all were over  age 100  !!!
2 boys and 2 girls...
superagers.com...
one guy still managing a hedge fund.... at an age over 100!!

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centenarians interaction witht the enviro

enviro risk but look at facts;  of his group of cents:

overweight  48% men and 44%  women
smoking  men 60%  women 30%
vegetarians  only 2.6%  !!!!!
one sister  smoked for 95 years...

jay leno  clip  (albert einstein)

secret to a long life (jokes Jay Leno) is more partying, drinking, and no exercise...

*****

a major barrier to conducting a study of centenarians...
who is the control group?

The cohort assembled to date  = longevity  is unique... so, look at their KIDS!!
then do age and gender match  (control group is people who are not relatd to centenarians...

so  offspring  of centenarisn are enriched with longevity  phenotypes and genotypes

these were all Ashkenzi Jews....

he shows an Illumina slide  across 16 european ethnic groups...

offspirng are less likely to have age-related disease than controls...

study from JAGS 2004...

btwn age 60 and 100.. almost everybody dies... so, there is a huge change in genotype going from 60 to 100
because of huge selection...

so  some genes are killing off people = killing genes and some genes are preserving them = longevity genes...

as a researcher you want to find the killing genes becoming less  freq and the  longev genes increasing
 (thats what u want to c in ur centenarians)

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first gene  func mutation in  IGF receptor  eg  higher plasma  IGF-1 levels  (small effect)
high adiponectin level  (really important)  highest levels r in centenarians.
cenetarins   have HIGH TSH and low thyroid  (important)  their thyrox is lowish...

FOXO3A  pronounced  FOXO  -3A...  validated by 8 groups...

CETP  is important modulates  HDL and  HDL particle size..
if decr  CEPT then u get  decr HDL...

twice as many people with this polymorphism in cents.

if  you are homozygous for this polymorphism then ur mortality is decr by 38%.

****
are longevitgy genes protective against one or several age-rel diseases?

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CETP VV genotype and cog function...

do  MMSE  =  mini-mental status exam...  improved correlated wth incr preval of  VV CETP genotype...

see JAMA  2010  sanders et al  vol 13
Sanders et al  2010 in JAMA...

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Klotho  is  a killing genotype
it drops from 40% prev at age 55 down to 15% at age  75 to 84  but then INCREAES preval to age 104???
what the hell???

so,  the longevity gene  buffering or mitigating the effect of the killing gene?

fre1 trend of deleterious gentype in Lp

goes from 20% at age 73  down to 10% age  age 75  but then increases  prevalence!!! in older folks...

possible explanation...  the Lpa  bad geneotype is over-ruled by the favorable longevity gene CETP VV.

****
all of Merck, Lily, and Roche are developing  CETP inhibitors
(Pfizer  tried with torcetrapid and failed)

Nov 17 2010  NEJM  raises good HDL chol by 138%
cuts bad chol 40% in patientson statins  etc.    get this paper.

*****
How can we ID  longevity genes with an un-biased approach?
ask Stuart Kin at Stanford

sl  manhattan plot for longevity  GWAS  affi 6.0
off 100 year olds vs 70 year olds  N = 350 in each group..

pic  of 100 year old...no glasses, no gray hair, no hearing aids... great skin

collab with Anne L. S. Chang MD at Stanford
aging skin...   as a phenotype... who looks the youngest...

 GWAS  for longevity (snps with p < 10**-6)
lots of unknown genes...

sl  epigenetics  (C-G methylation) and human's  aging  (from Gil Atzman)

comparision btwn 65 yo and 95 year olds.... huge difference in epigenetics...

looking at miRNA related to epigenetics....

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he spells it MITOCHINES    pronounced  mitokines...
he collabs iwth Pinchas Cohen...

hypothesis

mitochondria  has 13 peptides...

but there are apoptotic signals from the nucleus...

there are numerous nuclear peptides delivered to the mitochondria...

medial basal hypothalamus is an important center for control of  metab/ energetics .

to be mitochines.... he lists properties...

First mitochine isolated:  Humanin = HN

originally cloned as a protective factor in alzheimers diease...

highest tissue expression is in testes and brain...

give humanin  to a diabetic animal and it normalizes  glucose!

HN is an insulin secretogogue...

it protects against atherosclerosis...

HN assay  is higher in offspring of centenarians... and also  decr in alzheim pts.

he has a company thats working on this...

hypthalmus  MBH = medial basal hypthal is the central site for regulation of energy balance  (expenditure and
appetite...

SHLPS  prnounced  schleps...

humanin like peptides...

*****

take  home messages...

mechs by which longevity genes protect against aging can be ID'd.

whole genome sequencing and epigenetics are  the next horizons

and mitochines may have a physio role....

Q  abt  thyroid in centenearians... do they have hashimotos
A:  NO  those r excluded...  TSH is elevated  cuz  their T4 is lowish...

Q  epigenetics
A  use lymphoblasts for discovery;

his collab at Stanford is Anne L. S. Chang

his projects

Longevity Gene Project
and LonGenity

funded by Ellison  Med Fnd...