Human Supercentenarian Epidemiology and the Implications for Longevity Medicine Strategies for Engin

1
Human Supercentenarian Epidemiology and the
Implications for Longevity MedicineStrategies
for Engineered Negligible
SenescenceL. Stephen Coles,
M.D., Ph.D.UCLA School of MedicineLos Angeles,
California USAE-mail scoles_at_ucla.edu URL
http//www.grg.org Monday, September 22, 2003
300 315 PMInternational Association of
Biomedical Gerontology 10th CongressQueens
College Cambridge University UK 4 Days 75
Speakers 270 Attendees 27 Countries
2
Demographics of Centenarians

• In 1990, it was estimated that there were 37,306
  Centenarians in the United States (28,000 may be
  more accurate, accounting for the likelihood of a
  large number of false claims)
• In 2000, the US 2000 Census Report counted 50,454
  Centenarians in the United States (out of 281.4
  million Americans) (more than 450,000
  worldwide)(However, 42,000 may be more accurate,
  again accounting for the extensive number of
  false claims)
• By 2050, the Census Bureau estimates that the
  number of US Centenarians will grow to 834,000
  and double every ten years thereafter
• ______________________________________________
  __________________
• The 2000 Census counted 1,388 Supercentenarians
  (persons gt 110 years). However, the SSA has
  only about 140 such persons on their rolls.  Of
  these 140, at least one-third (and maybe
  more) are exaggerated claims.  Thus, the true
  number of US Living Supercentenarians is probably
  closer to 75 - 100. As of September
  22, 2003, the GRG validated --- with rigorous
  documentation --- just 18 Living US
  Supercentenarians
  (43 Supercentenarians throughout the entire world
  Gender Ratio 38
  females 5 males)

3
Demographics of Centenarians

4
Madame Jeanne Louise CalmentDied on August 4,
1997 at Age 122-- The Worlds Oldest Person
(Documented by The Guinness Book of Records)
Age 40 Age 120

5
Progressive World Record Holders

6
Mrs. Kamato Hongo of Japan Age 116 born
September 15, 1887

7
Mrs. Maud Farris Luse Age 115January 21, 1887
- March 18, 2002

8
John I. McMorran Age 113June 19, 1889 -
February 24, 2003 Movie at http//www.grg.org/JM
cMorran0.htmJohn at 111 and then
with Mr. Scott McMorran, his 39 yo Great Grandson
9
Mrs. Elma Grace Corning of Los Angeles Age 111
born February 22, 1892

• with her son
  Russell, age 87

10
Four More Los Angeles Supercentenarians
Mrs. Mage Russell, 110 Mrs. Marion Higgins,
110 Mrs. Mollie Beard, 110 (Died) Mr.
Gerald Gilman, 110

11
Supercentenarian Phenotype(The Struldbruggs in
Gullivers Travels by Jonathan Swift)

• Old, Decrepit, Sick Folks
• Deaf (Hard of hearing, correctable by bilateral
  hearing aids)
• Blind (Macular Degeneration, uncorrectable by
  eyeglasses or cataract surgery)
• Smell, Taste, Touch, suspected decreased
• Bad Teeth (Dentures)
• Frailty, Sarcopenia (confined to bed or a wheel
  chair)
• Skin (Stiff, Leathery Tissue-Paper Thin)
• Poor Orientationx3 (Neurodegenerative disease,
  Senility or Dementia) (But Excellent Long-Term
  Memory)
• Virtually never needed to see a doctor before age
  90
• No Autopsy (Necropsy) Data yet

12
43 Living Supercentenarian38 females and 5
males (as of September 22, 2003)

• Name Nationality Gender Race Age
  (Years) Date-of-Birth
• Kamato Hongo Japan F
  O 116 Sept 16, 1887
• Yukichi Chuganji Japan M
  O 114 Mar. 23, 1889
• Mitoyo Kawate Japan F
  O 114 May 15, 1889
• Elana Slough U.S. (NJ) F F
  114 July 8, 1889
• Charlotte Benkner U.S. (OH) F W
  113 Nov. 16, 1889
• Joan Riudavets Spain M W
  113 Dec. 15, 1889
• Aurelia Marotta U.S. (MA) F W
  113 June 27, 1890
• Hendrikje Van Andel Netherlands F W
  113 June 29, 1890
• Mary Crombie U.S. (IL) F W
  113 July 6, 1890
• Emma Verona Johnston U.S. (OH) F W
  113 Aug.  6, 1890
• Ura Koyama Japan F O
  113 Aug. 30, 1890
• Susie Gibson U.S. (AL) F W
  112 Oct. 31, 1890

13
43 Living Supercentenarians(as of September 22,
2003 Contd.)

• Name Nationality
  Gender Race Age (Years) Date-of-Birth
• 13. Mise Ito Japan F O 112 Nov.  6, 1890
• Fred Hale U.S. (NY) M W 112 Dec.  1, 1890
• Sawayo Tanaka Japan F O 112 June  9, 1891
• Grace Thaxton U.S. (KY) F W 112 June 18,
  1891
• Julie Winnefred Bertrand Canada (Que) F W 111
  Sept. 16, 1891
• Christine Hall U.S. (IL) F W 111 Dec.  3,
  1891
• Gladys Hawley England (UK) F W 111 Dec. 18,
  1891
• Virginia Dighero-Zolezzi Italy F W 111
  Dec. 24, 1891
• Agnes Rich U.S. (GA) F W 111 Jan. 20, 1892
  
• Tsuru Fukuhara Japan F O 111 Feb. 10, 1892
• Yutaka Endo Japan F O 111 Feb. 15, 1892
• Elma Grace Corning U.S. (CA) F W 111 Feb.
  22, 1892

14
43 Living Supercentenarians(as of September 22,
2003 Contd.)

• Name Nationality
  Gender Race Age (Years) Date-of-Birth
• Yoki Yonehara Japan F O 111 Mar. 2, 1892
• Maria Muraro Italy F W 111 Mar. 29, 1892
• Lucy D'Abreu Scotland F IW 111 May 24, 1892
• Kame Higa Japan F O 111 June 22, 1892
• Mary Ellen Swan Canada (Ont) F W 111 June 24,
  1892
• Anders Engberg Sweden M W 111 July 1, 1892
• Haru Shimazu Japan F O 111 July 7, 1892
• Salvina Martinelli Avanzi Italy F W 111 Aug.
  2, 1892
• Lilla De Geronimi-Zinara Italy F W 110 Dec. 
  2, 1892
• Anne-Marie Vandermersch Belgium F W 110 Dec.
  14, 1892
• (Eleanor) Maebelle Plant U.S. (FL) F W 110
  Feb. 25, 1893
• Litta Walker U.S. (NE) F W 110 Mar. 23, 1893

15
43 Living Supercentenarians(as of September 22,
2003 Contd.)

• Name Nationality Gender
  Race Age (Years) Date-of-Birth
• Lydia Newton U.S. (AZ) F W
  110 Mar. 23, 1893
• Minnie Kearby U.S. (IN) F W 110
  April 14, 1893
• Hermann Dornemann Germany M W 110 May 27,
  1893
• Grace Rebecca Jones U.S. (VA) F W 110 June
  4, 1893
• Gesuina Donati Italy F W 110 June 8,
  1893
• Lena Dionne U.S. (FL) F W 110
  June 14, 1893
• Marion Higgins U.S. (CA) F W 110
  June 26, 1893
• Check http//www.grg.org/calment.html
• 
  for the most recent updates.

16
Table of Supercentenarian Population Trends
ranging from August 1966 - September 2003

• Absolute Numbers Not Per Capita

17
Estimated World Population 1650 2000

• Cohort Size Increased by 400 Million

18
Demographics of Supercentenarians

• Our number of 43 Supercentenarians world-wide is
  based on validated cases, for which there are
  relatives willing to provide us with
  documentation (our cases frequently outlive their
  relatives)
• In 1990, the US Census Bureau reported that there
  were 2,700 sic Supercentenarians
• In 2000, they reported only 1,400
  Supercentenarians (About half of the errors were
  eliminated by comparing the Date-of-Birth with
  claimed Age, which were the result of people who
  didnt know how to do arithmetic Sigh!)
• In 2002, the SSA admitted that there were
  actually 139 persons age 110 or over receiving
  Social Security benefits
• Because most of these cases are exaggerated, the
  true number is more likely to be between 75 and
  100 persons
• No conclusions about whether these numbers over
  the last forty years are actually growing on a
  per capita basis can be made at this time

19
Can We Better Estimate the True Number of
Supercentenarians?

• The total number Supercentenarians cited above
  has been frequently been misconstrued in the news
  media as representing every single person in the
  world aged 110 and over.  The actual estimated
  number of worldwide living Supercentenarians is
  more likely to be between 300 - 450 persons. 
  For the USA, we predict something like 60 - 75
  Supercentenarians. 
• While the total number of validated cases
  cited earlier is only about ten percent  of the
  suspected real-world total, it should also be
  noted that the bulk of the true Supercentenarians
  actually fall between 110 - 113 years old
  hardly any ever survive to live past 115.  Our
  estimate of 300 - 450 persons is based on a
  survival percentage of centenarians-to-age-110 to
  be  between 0.15 - 0.25 percent.
• It should be noted that a significant majority of
  worldwide claimants to be age 110-or-over have
  subsequently been proven to be false 
  these individuals and more often their family or
  friends have their own personal motives
  for claiming these persons and, we are sad to
  report, are occasionally disingenuous (not
  well-intentioned).

20
U.S. Life Expectancy with Age by gender
for the Year 2000Source "Deaths Leading
Causes for 2000," and "Deaths Final Data for
2000" NVSR, Vol. 50, Nos. 15 and 16 (PHS)(CDC,
National Center for Health Statistics Atlanta,
GA September 16, 2002).

21
Is the Number of Supercentenarians Really
Increasing (per capita)?

• We believe that the increasing number of true
  cases that we have observed during the last 40
  years are the result of at least two factors
• better methods of identifying and documenting
  these individuals, not to mention  the diligence
  of our own committee members throughout the world
  who deserve much  of the credit and
• far more persons are reaching 110 than ever
  before. That is, people who were dying at 105 -
  109 are now reaching 110 - 113 years of age.
• Please note that the SSA data show that both of
  these reasons are major factors, and that it
  would be incorrect to ascribe all of the increase
  to an actual increase in longevity or all of the
  increase due to better record-keeping.  Coming in
  the next few months, an SSA Report, along with
  our own historical databases, will better show
  how much of the increase can be ascribed to each
  of these two factors.
• Finally, there is no statistical evidence to
  support the hypothesis that the absolute number
  of Supercentenarians is increasing as a
  percentage of the total population, although
  there is some evidence from animal studies that a
  reduction in the force of evolution after age 90
  changes our mortality from an exponentially-increa
  sing rate to a constant rate in the oldest old
  31.  This has become an important area of
  research in biodemography, and the answers are
  not in yet 32.

22
Is there a Mortality Plateau?

• When a species vitality due to the Force of
  Natural Selection goes from 100 percent (at
  puberty) to zero percent it cannot go negative
  (post menopause or reproductive competence
  modulo any grand-parenting effect), the
  mortality rate is transformed from an exponential
  function to a linear function, creating a knee
  or plateau in the upward log mortality
  regression line. For humans, this appears to
  happen at about age 95. In other words, if you
  manage to make it to age 95, the rate of
  mortality seems to ease off a little bit,
  allowing Centenarians to live quite a bit longer
  than they otherwise should.

23
Is There a Mortality Plateau at the Oldest
Ages?

• The observation of a mortality plateau or
  mortality deceleration could be due to one or
  both of two different hypotheses 32
• Genetic Heterogeneity Over time, individuals
  with the lowest death rates will populate a
  single congenic cohort, because other cohorts
  with higher death rates will already be
  extinguished.
• Natural Selection There will be a leveling of
  mortality rates at advanced ages due to a
  diminished evolutionary force of natural
  selection.

24
Validation of Exceptional Longevity, Odense
Monographs on Population Aging, Vol. 6 (Odense
University Press 1999)

25
Scientific Centenarian Study Groups Throughout
the World

• Country Principal Investigator(s)
  Institution(s) Approximate
• 
  Number of
  Centenarians Studied
• 1. USA Dr. Tom Perls, MD New England
  Centenarian Study
• Boston University Boston, MA
  650
• 2. USA Dr. Leonard Poon, MD University of
  Georgia 140
• 3. France Drs. Jean-Marie Robine and Michel
  Allard
• IPSEN Foundation
  
  900
• 4. France Drs. Robine and James Vaupel
• Supercentenarians Database
  INSERM, Montpellier 35
• 5. Italy Dr. Claudio Franceschi
• National Research Council and
  Ministries 2000
• 6. Denmark Dr. Bernard Jeune Odense University
  275
• 7. China Dr. Zeng Yi and James Vaupel
• The Chinese National Research
  Center on Aging
• Peking University and Duke
  University NIH
• Max Plack Institute for
  Demographic Research 4900

26
Six Blind Men and the Elephant

• Body Wall Tusk Spear Trunk Snake
  Leg Tree Ear Fan Tail Rope

27
.Cherubim with Flaming Sword who Guards the East
Gate to the Garden of Eden. Osiris, God
of Immortality, celebrated in The Egyptian Book
of the Dead, Husband of Isis,
Brother of Seth, in Tomb of Tutankhamen. Ponce
de Leon in Florida 1460 - 1521 Two Alchemists
c. 1740. The Rosetta Stone (Hieroglyphics,
Demotic, and Greek) 196 B.C. found July 1799
A.D. (Antediluvians Methuselah)

28

We simply dont know the right stuff (Trinity
College Dublin, IRELAND)
29
Homo sapiens First Lived in Ethiopia, Central
Africa 160,000 Years Ago

30
Free-Radical Oxidative Stress is Like the Damage
from Wind and Water Erosion on the Pyramids
31
So What is the Centenarians Secret?

• LINK?
• Why do Supercentenarians live so long?
• Not because they dont age. Indeed, they do age.
  
• But because they seem to age more uniformly (not
  more slowly)
• They received a fortuitous genetic roll of the
  dice in a stochastic process that left no
  conspicuous weak links in their chain

32
Three Possible Life Histories for a Human Being
(slopes a, b, c)

• Resembles a roller coaster ride at the end of
  life
• Biological Warranty Period 0 55 years
• S. Jay Olshansky, University of Chicago

33
Strategy for Doubling Maximum Lifespan
Recapitulation of Development

• Adult Stem Cells in situ must be stimulated to
  undergo fresh organogenesis, in the context of an
  adult organism (constrained by the architecture
  of our pre-existing tissues, which risk being
  obliterated by multiple, simultaneous teratomas
  if we didnt do it right)(need systematic
  apoptosis)
• Nature has never been observed to do this, so
  there are no model organisms to guide us (Sigh!)
• Were at the Need-for-Blood-Transfusion in 1800
  stage of solving this problem we need to learn
  the signaling language of stem-cell
  communication in the absence of instruction,
  stem cells are stupid

34
The Human Genome (February 2001)

35
Dr. Craig Venter, The Center for Advancement of
Genomics Dr. Francis Collins, NIH
36
Genomic Sequences of Species National Human
Genome Research Institute (NHGRI) Dr. Francis
Collins, Director and Dr. Alan Guttmacher, Deputy
Director -- Genome Resources and Sequencing
Priority Panel (Prof. William Gelbart of Harvard
University, Chairman)

37
But Genetic Engineering is Slow

• To date, some 1,150 human-disease genes have been
  discovered, but only a few have led to a cure.
  Only one, for CML (Chronic Myelogenous Leukemia),
  has reached the market. Delivery Vectors are a
  problem.
• Genomics 25 30,000 human genes
• Genetic homology among all mammals 99 percent
  
• Proteomics 200-300,000 human proteins
• Harvard Center for Genomics Research, TIGR,
  Celera Genomics, Lawrence Livermore, and Sandia
  National Laboratories (DOE)(Developing Parallel
  Architecture Blade Servers running the Linux OS
  with Clusters of Standard Processors executing
  parallel BLAST)(ASCI Q)
• IBMs Blue Gene Supercomputer (100 million
  100x faster) to solve the protein folding
  problem

38
Aristotles Treatise on Animals Book III c.
330 B.C.
39
Fetal Development of Left Hand Post Web
Apoptosis
40
Embryogenesis is a Computer Program (without
Do-Loops)

• The genome is executed
• like a set of dominos
• ready to fall over
• if any dominos are missing
• the program will fail.
• Then, there are no more
• dominos.

41
Tampering with Nature by
42
Technology Stem Cells High
magnification of an early embryo at the tip of a
needleScientific American, Vol. 285, No. 6, p.
27 (December 2001).
43
Three Important Unknown Questions about Stem Cells

• Are Adult Stem Cells as good as Embryonic Stem
  Cells?
• Is the Red Cross Blood Bank model of Type and
  Cross Match for a Stem-Cell Bank good enough to
  prevent rejection or must stem cells be
  autologous? Solving the problem of adult stem
  cells is sort of like solving the problem of
  blood transfusion in 1900 before the discovery of
  the ABO Typing System
• Are there chemokines available to turn adult stem
  cells on in situ? (and then turn them off)

44
Dr. Michael West, CEO,Advanced Cell
Technologyof Worcester, MA US News World
Report (December 3, 2001) and Scientific
American (January 2002).
45
Somatic Cell Nuclear Transfer in Humans
Pronuclear and Early Embryonic Development,
e-Biomed (November 26, 2001).
46
Dolly the Sheep, First Cloned Species 1996 -
2003

As of September 15, 2003, PPL Therapeutics, a
spinoff of the Roslin Institute has ceased
operations.
47
Table of Cloned Species

48
Prospects for Anti-Aging Interventions

• Pituitary Hormonal Rebalancing (1990)
• hGH (IGF-1, Hypothalamic/Pineal Secretagogues)
• Thyroid
• Sex Steroids and the Neuro/Endocrine Axis
• Telomere Shortening (Telomerase)(1996)
• Caloric Restriction (CR)(1998)(NIA 20M)
• Free Radicals (AntiOxidants and Cross-Link
  Breaker Drugs)(2000)
• Dissolvers for Lipofuscin Accumulation (2002)
• Immune Competence (Anti-Inflammation)
• Nanotechnology
• Adult/Embryonic Autologous/Generic Stem Cells
  (2003)
• All of the above Rearranging the deck chairs
  on the Titanic
• Continuously Reprogram the Genome

49
The Politics of Anti-Aging Therapeutics

• To argue that human life would be better without
  death is to argue that human life would be better
  without being human... The finitude of human life
  is a blessing for every individual whether he
  knows it or not."--- Leon R. Kass, M.D., Addie
  Clark Hardinig Professor at the University of
  Chicago, Chairman of President George W. Bush's
  Bioethics Council, and Shakespearean Master of
  apologism who coined the phrase The Wisdom of
  Repugnance.
• Refs p. 144, Nicholas Wade, Life Script
  How the Human Genome Discoveries Will Transform
  Medicine and Enhance Your Health (Simon
  Schuster, New York 2001).
• Mortality and Morality The Virtue of
  Finitude, (1983) Toward a More Natural Science
  Biology and Human Affairs, p. 308 (Free Press
  New York 1985).
• Editorial Remark We readily acknowledge
  that eliminating that form of death secondary to
  intrinsic aging would create a significantly
  different world than the one we are used to. But
  we respectfully disagree with Dr. Kass regarding
  its undesirability. In our view, being human is a
  condition that was thrust upon us (without our
  consent), and we see nothing intrinsically sacred
  about retaining the form of a mortal human being.
  If nothing else, Nature has proven herself to
  be ruthlessly experimental. We see no reason why
  we should not take some risks and do a few
  experiments of our own. After all, without such
  experimentation, there is no other certainty but
  death.

50
Otherwise, the Doctors Magic Wand or the Grim
Reaper Awaits with his Scythe and Hour Glass

51
We Need a Bridge Plan to Get Us to the Other
Side

• 'Bridge of Hope' by Thomas Kinkade
• Media Arts Group, Inc. Morgan Hill, California

52

• ACKNOWLEDGEMENTS
• An abbreviated list of the 45 Committee members
  and their associated staff includes the
  following
• Mr. Louis Epstein, Chairman of the
  Supercentenarian Committee, NY USA
• Mr. Robert Young of Atlanta, GA USA
• Dr. Tom Perls, Director of the NECS affiliated
  with Boston University, Boston, MA USA
• Dr. Leonid Gavrilov of the University of Chicago,
  IL USA
• Dr. Leonard Poon of Georgia who directs another
  Centenarian Study for the South, GA USA
• Dr. Tom Johnson of the University of Colorado,
  CO USA
• Dr. Steven Austad, Zoologist from the University
  of Idaho, ID USA
• Dr. John Wilmoth a Demographer from UC Berkeley,
  CA USA
• Mr. Johnny Adams Los Angeles Gerontology
  Research Group, CA USA
• Dr. Bertrand Desjardins and Mr. Robert Bourbeau
  CANADA
• Mr. Thatcher, Registrar General for England and
  Wales UK
• Dr. M. Poulain Mr. Dany Chambre Mr. Bart
  Versieck BELGIUM
• Mr. Giovanni Alunni Rome, ITALY
• Mr. Gert Jan Kuiper NETHERLANDS
• Dr. Bernard Jeune of Odense University DENMARK
• Mr. Foti Tillo SWEDEN
• Mr. Dag Hoelseth NORWAY

• Thank you

• Thank you

• Thank you

53
Our Scientific Legacy(Open Notes for Names)

54
REFERENCES

• S. Jay Olshansky, Bruce A. Carnes, and Aline
  Desesquelles, "Prospects for Human Longevity,"
  Science, Vol. 291, No. 5508, pp. 1491-2 (February
  23, 2001). 
• Ronald Lee, Predicting Human Longevity,
  Science, Vol. 292, No. 5522, pp. 1654-55 (June 1,
  2001).
• 3. Leonard Hayflick, "The Future of Aging,"
  Nature, Vol. 408, pp. 267-269 (November 9,
  2000). 
•  

55
REFERENCES (Contd.)

• Robert Koenig, "Demography Sardinia's Mysterious
  Male Methuselahs," Science, Vol. 291, No. 5511,
  pp. 2074-6 (March 16, 2001).
• Damaris Christensen, "Making Sense of
  Centenarians Genes and Lifestyle Help People
  Live Through a Century," Science News, Vol. 159,
  pp. 156-7 (March 10,2001).
• 6. Nir Barzilai, Ilan Gabriely, Magda
  Gabriely, Nancy Iankowitz, and John D. Sorkin,
  "Offspring of Centenarians Have a Favorable Lipid
  Profile," Journal of the American Geriatrics
  Society, Vol. 49, No. 1, pp. 76-79 (January
  2001).

56
REFERENCES (Contd.)

• 7. Tom T. Perls, E. Burbrick, C. G. Wagner, et
  al, "Siblings of Centenarians Live Longer,"
  Lancet, Vol. 351, p. 1560 (1998).
• 8. Jean-Marie Robine and M. Allard, "The Oldest
  Human," Science, Vol. 279, p. 1834 (1998).
• 9. Jean-Marie Robine, "A New Biodemographic
  Model to Explain the Trajectory of Mortality,"
  Symposium on Organisms with Slow Aging (SOSA),
  ed. by Caleb E. Finch and Robert E. Ricklefs,
  USC/UCLA Center on Biodemograhy (Los Angeles,
  California September 22-23, 2000). 

57
REFERENCES (Contd.)

• 10. Jean-Marie Robine and James Vaupel,
  "Supercentenarians, Slower Aging Individuals, or
  Senile Elderly?" Symposium on Organisms with Slow
  Aging (SOSA), ed. by Caleb E. Finch and Robert E.
  Ricklefs, USC/UCLA Center on Biodemograhy (Los
  Angeles, California September 22-23, 2000).

58
REFERENCES (Contd.)

• 11. Jean-Marie Robine, Thomas B. L. Kirkwood,
  Michel Allard, Eds., Sex and Longevity
  Sexuality, Gender, Reproduction, Parenthood
  
  (Springer-Verlag, New York, 2001).
• 12. Bernard Jeune and James W. Vaupel, Eds.,
  Validation of Exceptional Longevity, Odense
  Monographs on Population Aging, Vol. 6 (Odense
  University Press ISBN 8778384664 249 pages
  1999).

59
REFERENCES (Contd.)

• 13. Annibale A. Puca, Mark J. Daly, Stephanie J.
  Brewster, Tara C. Matise, Jeffrey Barrett,
  Maureen Shea-Drinkwater, Sammy Kang, Erin Joyce,
  Julie Nicoli, Erica Benson, Louis M. Kunkel, and
  Thomas T. Perls, A Genome-Wide Scan for Linkage
  to Human Exceptional Longevity Identifies a Locus
  on Chromosome 4, Proceedings of the National
  Academy of Sciences, USA, Vol. 98, Issue 18, pp.
  10505-8 (August 28, 2001).

60
REFERENCES (Contd.)

• 14. Lana Skirboll, Editor, "Stem Cells
  Scientific Progress and Future Research
  Directions -- Opportunities and Challenges A
  Focus on Future Stem Cell Applications" (200 page
  NIH Report June 19, 2001).
• 15. Bert Vogelstein, Barry R. Bloom, Corey S.
  Goodman, Patricia A. King, Guy M. McKhann, Myron
  L. Weisfeldt, and Kathleen R. Merikangas, Stem
  Cells, and the Future of Regenerative Medicine
  (Committee on the Biological and Biomedical
  Applications of Stem-Cell Research National
  Academy of Sciences Press Washington, D.C.
  September 11, 2001).
• 16. Daniel R. Marshak, Richard L. Gardner, and
  David Gottlieb, eds., Stem Cell Biology (550
  pages Cold Spring Harbor Laboratory, NY 2001).

61
REFERENCES (Contd.)

• 17. Jose B. Cibelli Ann A. Kiessling Kerrianne
  Cunniff Charlotte Richards Robert P. Lanza
  Michael D. West, "Rapid Communication Somatic
  Cell Nuclear Transfer in Humans Pronuclear and
  Early Embryonic Development," e-Biomed The
  Journal of Regenerative Medicine, Vol. 2, pp. 25
  - 31, DOI 10.1089/152489001753262168 (Mary Ann
  Liebert, Inc, November 26, 2001).
• 18. Jose B. Cibelli, Robert P. Lanza, Michael D.
  West, and Carol Ezzell, The First Human Cloned
  Embryo, Scientific American, pp. 44-51(January
  2002).
• 19. Leonid A. Gavrilov and Natalia S. Gavrilova,
  The Reliability Theory of Aging and Longevity,
  Journal of Theoretical Biology, Vol. 213, No. 4,
  pp. 527-545 (2001).
• 20. John C. George, et al, Age and Growth
  Estimates of Bowhead Whales (Balaena mysticetus)
  via Aspartic Acid Racemization, Canadian Journal
  of Zoology, Vol. 77, pp. 571-580 (1999).

62
REFERENCES (Contd.)

• 21. Ronald McKay,. et al. "Dopamine Neurons
  Derived from Embryonic Stem Cells Function in an
  Animal Model of Parkinson's Disease," Nature,
  Vol. 417 (June 20 2002).
• 22. Catherine M. Verfaille, et al. "Pluripotency
  of Mesenchymal Stem Cells Derived from Adult
  Marrow," Nature, Vol. 417 (June 20 2002).
• 23. Thomas T. Perls, John Wilmoth, Robin
  Levenson, Maureen Drinkwater, Melissa Cohen,
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Cartoon from The New Yorker

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