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  Outline For Research
Science at Work

Version 2.19                                                                                          11/30/06

The Supercentenarian Research Foundation (SRF) has been formed to promote and fund research into aging.  Initially the research will emphasize supercentenarians, but will also include their first-degree relatives (children, siblings, and parents) as well as younger age groups.  Investigation of chimpanzees may also be undertaken.  Key questions to be answered are:  Why do supercentenarians live longer than most people?  Why don't they live longer than they do?  The SRF endeavor will consist of three overlapping phases:

  1. Obtain biological samples from living supercentenarians by non-harmful means plus tissue samples during autopsies
  2. Fund research to characterize the biological state of subjects down to the cellular and molecular level
  3. Fund research into potential modalities to prevent, alleviate, and reverse the causes and effects of aging.

In order for the SRF to succeed in its objectives (please see the Mission Statement) a solid Research Plan that is endorsed by scientists of gerontology is essential for credibility in the solicitation for donations. We are grateful to the following individuals who have contributed to the development of this Plan:

Andrzej Bartke, Ph.D., University of Southern Illinois
Robert Cockrell, M.D.
L. Stephen Coles, M.D., Ph.D., Gerontology Research Group
Craig A. Cooney, Ph.D., University of Arkansas
Ana Maria Cuervo, M.D., Ph.D., Albert Einstein College of Medicine
Christian Dumpitak, Ph.D., Heinrich-Heine Universitaet Duesseldorf
Barry Flanary, Ph.D., Phoenix Biomolecular Corporation
David Gobel, Executive Director of the Methuselah Foundation
Aubrey de Grey, Ph.D., University of Cambridge
Philip N. Hawkins, Ph.D., Royal and Free University College Medical School
Michal Jazwinski, Ph.D., Louisiana State University
Gunther Kletetschka, Ph.D., Goddard Space Flight Center/NASA
George Martin, M.D., University of Washington
Vincent Monnier, M.D., Case Western Reserve University
Graham Pawelec, Ph.D., University of Tubingen
Mark B. Pepys, M.D., Ph.D., Royal and Free University College Medical School
Stanley R. Primmer, M.A.
Karlis Ullis, M.D.
Jan Vijg, Ph.D., Buck Institute
Huber Warner, Ph.D., University of Minnesota

Additional contributions are much needed to complete the Research Plan. The following outline suggests elements that may be included in this plan, but we need your help to fully develop it.  Please write a page on how research should be conducted for the items of your particular interest or expertise.  Include an estimate of the cost to perform the research discussed.  Then please send your comments, criticism, modifications, and/or expansion of this outline plus your more completely stated definition of the specific sections of your choice to:

A. Non-Harmful Procedures for Living Persons

  1. Continued collection of data on who supercentenarians are and the validation of their ages
  2. Collection of data on offspring, siblings, and, to the extent possible, parents of supercentenarians
  3. Expansion of data collection to individuals younger than 110, particularly men
  4. Obtain medical and life style data on identified subjects via interviews with supercentenarians, their family members, and their physicians
  5. Obtain buccal swabs for:
    1. Hormone analyses
    2. DNA analyses
  6. Examination for oral health
  7. Examination of eyes
    1. Measure of visual accommodation with H-Scan
    2. Examine for light sensitivity and pupil constriction
    3. Examine for cholesterol deposition
    4. Test for glaucoma
    5. Examine for glycation and lens hardening
    6. Examine for cataracts
    7. Examine retina for fluorescence indicating macular degeneration
    8. Macular pigment optical density
    9. Visual acuity
    10. Contrast sensitivity
    11. Glare recovery
    12. Examination of fundus photos for diabetic retinopathy
  8. Examination of ears and hearing
  9. Examination of nose and olfactory sensitivity
  10. Examination of throat
  11. Determination of cognitive status
    1. Brain analysis by p300 latency
    2. Memory tests
    3. Psychological analyses
    4. Psychosomatic analysis
    5. Differentiate between vascular dementia and Alzheimer’s disease
  12. Stool analyses
    1. Analysis for cancer mutations
    2. Other analyses
  13. Urinalysis
    1. Examine for oxidized nucleic acids
  14. DNA analyses
    1. Sequence of DNA
    2. SNP analysis
    3. Examination of DNA for longevity-associated gene polymorphisms (see below under Post Mortem Research 3.g.)
  15. Blood sampling
    1. Lipid profile analysis
    2. Cholesterol analysis
    3. C-Reactive Protein
    4. Homocysteine
    5. Fibrinogen
    6. APOA isoforms
    7. APOE isoforms
    8. Lp-PLA2
    9. IL-6
    10. HSP-70
    11. TNF-a
    12. Assessment of Immune Risk Profile
    13. Determination of CD4:CD8 ratio
    14. Determination of CMV status and other sources of chronic antigenic stimulation
    15. CD28
    16. Identification of dysfunctional CD8 cells by presence of double positive  KLRG-1 and CD57
    17. Glucose
    18. S-adenosylmethionine
    19. PSA analysis for men
    20. Determination of the cysteine/cystine and GSH/GSSG redox state
    21. Analyze the protein profile
    22. Analyze the metabolomic profile
  16. Measurement of blood pressure
  17. Determine the metabolic profile
    1. Perform analysis of their diet
    2. Inquire about their eating behavior
    3. Determine their caloric intake
  18. Insulin sensitivity
  19. Determine extent of sarcopenia
  20. Measure pulse rate
  21. Test reflexes
  22. Describe ability to walk
  23. Analysis of hair for toxic elements
  24. Examination of skin (note:  these analyses may have to be performed in post mortem tissue samples)
    1. Determine the functionality of stem cells in basal keratinocytes, if biopsies are not too harmful
    2. Determine the ratio of senescent to mitotically competent fibroblasts in the dermis
    3. Determine the condition of the extracellular matrix in the skin
  25. If transport to a medical facility is feasible, conducting PET, CT, ultrasound, EKG, MRI, and Functional MRI scans could be considered
  26. Comparison of current analyses with medical records of prior analyses
  27. Statistical analysis of accumulated data
  28. Protection of the privacy of subjects

B. Post Mortem Research

      (Note:  analyses requiring tissue collection within a few hours of death are preceded by *.)

  1. Autopsies
  2. Tissue collection and preservation
    1. Determine tissue types to be collected with special considerations required for each type
    2. Finalize protocols for tissue preservation (being developed by Greg Fahy)
    3. Finalize arrangements for tissue bank at UCLA (being arranged by L. Stephen Coles) and/or other locations
  3. DNA analyses
    1. Sequence of DNA
    2. SNP analysis
    3. Determination of extent of somatic DNA damage
    4. *Determination of the relative activity of DNA repair mechanisms, including PARP1 and the DNA-PK complex
    5. *Performance of microarray analyses to determine relative expression of mRNA and comparison to identical analyses from young individuals
    6. Determination of why some supercentenarians who have smoked didn't get cancer
    7. Examination of DNA for polymorphisms of specific genes previously found to be associated with longevity, such as:

    i.p53 [van Heemst D et al.  "Variations in Human TP53 Gene Affects Old Age Survival and Cancer Mortality," Exp Gerontol, 2005 Jan-Feb; 40(1-2):11-15]

   ii. CETP (cholesteryl ester transfer protein) [Barzilai N et al. "Unique lipoprotein phenotype and genotype associated with exceptional longevity," JAMA. 2003 Oct 15;290(15):2030-40]

  iii. MTP (microsomal transfer protein) [Geesaman BJ et al.  "Haplotype-based identification of a microsomal transfer protein marker associated with the human lifespan," Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14115-20]

  iv. mtDNA polymorphisms [Niemi AK et al.  "A combination of three common inherited mitochondrial DNA polymorphisms promotes longevity in Finnish and Japanese subjects." Eur J Hum Genet. 2004 Oct 13 - Epub ahead of print]

  v. ACE (angiotensin I converting enzyme) [Katzov H et al.  "A cladistic model of ACE sequence variation with implications for myocardial infarction, Alzheimer disease and obesity," Hum Mol Genet. 2004 Nov 1;13(21):2647-57]

 vi. PON1 (paraoxonase 1) [Rea IM et al.  "Paraoxonase polymorphisms PON1 192 and 55 and longevity in Italian centenarians and Irish nonagenarians. A pooled analysis," Exp Gerontol. 2004 Apr;39(4):629-35]

 vii. SIRT3 (sirtuin 3) [Rose G et al.  "Variability of the SIRT3 gene, human silent information regulator Sir2 homologue, and survivorship in the elderly," Exp Gerontol. 2003 Oct;38(10):1065-70]

viii. IGF-IR (IGF-I receptor) [Bonafe M et al.  "Polymorphic variants of insulin-like growth factor I (IGF-I) receptor and phosphoinositide 3-kinase genes affect IGF-I plasma levels and human longevity: cues for an evolutionarily conserved mechanism of life span control," : J Clin Endocrinol Metab. 2003 Jul;88(7):3299-304]

  ix. APOE (apolipoprotein E) [Panza F et al.  "Apolipoprotein E (APOE) polymorphism influences serum APOE levels in Alzheimer's disease patients and centenarians," Neuroreport. 2003 Mar 24;14(4):605-8]

  1. Determination of the occurrence or lack thereof of cancerous and precancerous tissues
  2. Determination of the contribution of cellular replicative senescence to the aged condition of tissues
  3. *Determination of the condition of intracellular long-lived proteins, including both A & B type lamins 
    1. Have they undergone oxidation, glycation, deamidation, nitration, or other alteration?
    2. Determination of the proportion of deformed nuclei when cells are not dividing.  Misshapen nuclei may indicate an imbalance in nuclear envelope proteins and/or fragility of the nuclear envelope.
  4. *Determination of the presence of inflammation in various tissues
  5. Determination of whether epigenetic changes caused a reduction in heterochromatin
  6. Determination of the methylation status of chromatin
    1. Is there a general decrease in methylation of chromatin in supercentenarians?
    2. Are the promoters of certain genes methylated, thereby affecting expression?
    3. Does the methylation or acetylation of specific residues in histones differ from younger individuals, and does this have epigenetic effects?
  7. *Determination of the status of multiple types of stem cells
    1. What is their proliferative capacity?
    2. Does this capacity depend on the condition of surrounding cells?
    3. Would this capacity be greater if the cells were cultured in association with young tissue than if with old tissue?
    4. What are their telomere lengths?
    5. Determine the condition of long-lived proteins in stem cells (as described above)
    6. Are stem cells more sensitive to stress than stem cells from younger individuals?  If so, why?
    7. Are limitations on the capacity of stem cells to replace lost cells a significant factor in aging?
    8. What limits this capacity?
  8. Determination of the status of the mitochondria, including:
    1. mtDNA sequence
    2. mtDNA mutations in both mitotic and postmitotic cells
    3. *Mitochondrial membranes and other components
    4. Are the mitochondria larger than normal?
    5. Redox potential
    6. Measurement of mtDNA content (per unit volume) of tissue in brain, muscle, heart, and liver
  9. Analysis of the lysosomal system
    1. Determination of the lipofuscin content of the lysosomes
    2. *Determination of protein turnover rate
    3. *Measurement of protease level and activity, including cathepsins
    4. Morphometric quantification of number of autophagic vacuoles
    5. Measurement of specific autophagy related proteins and genes

                                            i.     Beclin-1

                                           ii.     Atg 5

                                          iii.     Atg 12

                                         iv.     LCR

                                          v.     Mtor

    1. Quantification of lysosomes active for selective autophagy by levels of markers

                                            i.     Lamp2a

                                           ii.     Hsc70

  1. Examination for the presence of cytoplasmic aggregates
  2. *Determination of the status of other cellular components
  3. Determination of the status of the extracellular matrix (ECM)
    1. Is significant systemic amyloidosis present?
    2. Are significant advanced glycation end products (AGEs) present?  If so, which?
    3. What is the occurrence of harmful molecules secreted by senescent cells in the ECM, such as matrix metalloproteinase-3?
    4. Have other alterations of the ECM occurred?
  4. Determination of the extent of amyloid b deposits and tau tangles in the brain
  5. Investigation of prion protein (PrP)
    1. Investigation of potentially subclinical prion diseases
    2. Sequence the PRNP gene that encodes the PrP protein

                                             i.     Examine for potential polymorphisms of codon 129

                                           ii.     Investigate known mutations connected to familial forms of prion     diseases

                                         iii.     Investigate potential new polymorphisms that might contribute to   the stability of the cellular isoform of the prion protein

    1. Determine if tissues contain PrP-positive protein accumulations or deposits
  1. *Investigation of the degree of immunosenescence
    1. Determination of whether immunosenescence is general or clonal for particular pathogens
    2. What are the relative proportions of naive and memory T cells and B cells?
    3. Determination of the count of T cell receptor rearrangement excision circles, a biomarker of immunological aging
    4. What is the status of the thymus?
    5. What is the production of IL-7 in the thymus?
    6. What is the production of IL-7 in bone marrow stromal cells?
    7. What is the expression of CD28 for CD8 T cells?
    8. What is the fraction of replicatively senescent T cells and B cells?
    9. Determination of CD4:CD8 ratio
    10. Determination of CMV status and other sources of chronic antigenic stimulation
    11. Identification of dysfunctional CD8 cells by presence of double positive  KLRG-1 and CD57.
  2. Investigation of atherosclerosis
  3. Investigation of macular degeneration
  4. *Investigation of hormones
    1. Determination of the ability of pituitary cells to express growth hormone
    2. Determination of the ability of various cell types to express IGF-1
    3. Determination of the functionality of growth hormone and IGF-1 receptors
    4. Investigate secretion of other hormones and their receptors
  5. Corpora amylacea
    1. Determine the number, location, and size of corpora amylacea in the central nervous system and compare with other age groups
    2. Correlate the occurrence of corpora amylacea with the deposits of other misfolded proteins
    3. Determine the protein content of corpora amylacea
  6. Analysis of proteasome activities
  7. Analysis of accumulated data
  8. Meta-analysis of existing studies
  9. Protection of the privacy of subjects

C. Procedures for Intervention in Aging

  1. Determine methods for reversing sarcopenia
    1. Identify factors in serum of young mice that activate muscle satellite cells in old mice to repair injured muscles
    2. Determine if injection of identified factors into old mice enhance repair of injured muscles
    3. Determine cellular source of identified factors in young mice
    4. Determine cause of failure of cells in old mice to secrete the identified factors
    5. Identify molecular signals emitted by injured muscles in mice
    6. Determine if injection of signals simulating muscle injury plus factors that activate muscle satellite cells can reduce the effects of sarcopenia in aged mice
    7. Determine if human factors equivalent to those identified in mice can reverse the effects of sarcopenia in human muscle tissue in vitro
    8. Conduct clinical trials in supercentenarians of effects of sarcopenia reversing factors
  2. Determine effects of sarcopenia reversing factors on cell types other than muscle satellite cells