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:
- Obtain biological
samples from living supercentenarians by non-harmful means plus tissue samples during
autopsies
- Fund research to
characterize the biological state of subjects down to the cellular and molecular level
- 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
- Continued
collection of data on who supercentenarians are and the validation of
their ages
- Collection
of data on offspring, siblings, and, to the extent possible, parents of
supercentenarians
- Expansion
of data collection to individuals younger than 110, particularly men
- Obtain
medical and life style data on identified subjects via interviews with
supercentenarians, their family members, and their physicians
- Obtain
buccal swabs for:
- Hormone
analyses
- DNA
analyses
- Examination
for oral health
- Examination
of eyes
- Measure
of visual accommodation with H-Scan
- Examine
for light sensitivity and pupil constriction
- Examine
for cholesterol deposition
- Test
for glaucoma
- Examine
for glycation and lens hardening
- Examine
for cataracts
- Examine
retina for fluorescence indicating macular degeneration
- Macular
pigment optical density
- Visual
acuity
- Contrast
sensitivity
- Glare
recovery
- Examination
of fundus photos for diabetic retinopathy
- Examination
of ears and hearing
- Examination
of nose and olfactory sensitivity
- Examination
of throat
- Determination
of cognitive status
- Brain
analysis by p300 latency
- Memory
tests
- Psychological
analyses
- Psychosomatic analysis
- Differentiate between
vascular dementia and Alzheimer’s disease
- Stool
analyses
- Analysis
for cancer mutations
- Other
analyses
- Urinalysis
- Examine
for oxidized nucleic acids
- DNA
analyses
- Sequence
of DNA
- SNP
analysis
- Examination
of DNA for longevity-associated gene polymorphisms (see below under Post
Mortem Research 3.g.)
- Blood
sampling
- Lipid
profile analysis
- Cholesterol
analysis
- C-Reactive
Protein
- Homocysteine
- Fibrinogen
- APOA
isoforms
- APOE
isoforms
- Lp-PLA2
- IL-6
- HSP-70
- TNF-a
- Assessment
of Immune Risk Profile
- Determination
of CD4:CD8 ratio
- Determination
of CMV status and other sources of chronic antigenic stimulation
- CD28
- Identification
of dysfunctional CD8 cells by presence of double positive KLRG-1 and CD57
- Glucose
- S-adenosylmethionine
- PSA
analysis for men
- Determination
of the cysteine/cystine and
GSH/GSSG redox state
-
Analyze the protein profile
-
Analyze the metabolomic profile
- Measurement
of blood pressure
- Determine
the metabolic profile
-
Perform analysis of their diet
-
Inquire about their eating behavior
-
Determine their caloric intake
- Insulin
sensitivity
- Determine
extent of sarcopenia
- Measure
pulse rate
- Test
reflexes
- Describe
ability to walk
- Analysis
of hair for toxic elements
- Examination
of skin (note: these analyses may
have to be performed in post mortem
tissue samples)
- Determine
the functionality of stem cells in basal keratinocytes, if biopsies are
not too harmful
- Determine
the ratio of senescent to mitotically competent fibroblasts in the dermis
- Determine
the condition of the extracellular matrix in the skin
- If
transport to a medical facility is feasible, conducting PET, CT,
ultrasound, EKG, MRI, and Functional MRI scans could be considered
- Comparison
of current analyses with medical records of prior analyses
- Statistical
analysis of accumulated data
- Protection
of the privacy of subjects
B. Post Mortem Research
(Note:
analyses requiring tissue collection within a few hours of death are
preceded by *.)
- Autopsies
- Tissue
collection and preservation
- Determine
tissue types to be collected with special considerations required for
each type
- Finalize
protocols for tissue preservation (being developed by Greg Fahy)
- Finalize
arrangements for tissue bank at UCLA (being arranged by L. Stephen Coles)
and/or other locations
- DNA
analyses
- Sequence
of DNA
- SNP
analysis
- Determination
of extent of somatic DNA damage
- *Determination of the relative activity of DNA repair mechanisms, including
PARP1 and the DNA-PK complex
- *Performance
of microarray analyses to determine relative
expression of mRNA and comparison to identical analyses from young
individuals
- Determination
of why some supercentenarians who have smoked didn't get cancer
- 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]
- Determination
of the occurrence or lack thereof of cancerous and precancerous tissues
- Determination
of the contribution of cellular replicative senescence to the aged
condition of tissues
- *Determination of the condition of intracellular long-lived
proteins, including both A & B type lamins
- Have they undergone oxidation,
glycation, deamidation, nitration, or other alteration?
- 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.
- *Determination
of the presence of inflammation in various tissues
- Determination
of whether epigenetic changes caused a reduction in heterochromatin
- Determination
of the methylation status of chromatin
- Is
there a general decrease in methylation of
chromatin in supercentenarians?
- Are
the promoters of certain genes methylated,
thereby affecting expression?
- Does
the methylation or acetylation
of specific residues in histones differ from
younger individuals, and does this have epigenetic effects?
- *Determination
of the status of multiple types of stem cells
- What
is their proliferative capacity?
- Does
this capacity depend on the condition of surrounding cells?
- Would
this capacity be greater if the cells were cultured in association with
young tissue than if with old tissue?
- What
are their telomere lengths?
- Determine
the condition of long-lived proteins in stem cells (as described above)
- Are
stem cells more sensitive to stress than stem cells from younger
individuals? If so, why?
- Are
limitations on the capacity of stem cells to replace lost cells a
significant factor in aging?
- What
limits this capacity?
- Determination
of the status of the mitochondria, including:
- mtDNA
sequence
- mtDNA
mutations in both mitotic and postmitotic cells
- *Mitochondrial
membranes and other components
- Are
the mitochondria larger than normal?
- Redox
potential
- Measurement
of mtDNA content (per unit volume) of tissue in brain, muscle, heart, and
liver
- Analysis
of the lysosomal system
- Determination
of the lipofuscin content of the lysosomes
- *Determination of protein turnover rate
- *Measurement
of protease level and activity, including cathepsins
- Morphometric
quantification of number of autophagic vacuoles
- Measurement of specific autophagy
related proteins and genes
i. Beclin-1
ii. Atg 5
iii. Atg 12
iv. LCR
v. Mtor
- Quantification of lysosomes
active for selective autophagy by levels of
markers
i. Lamp2a
ii. Hsc70
- Examination for the presence of cytoplasmic aggregates
- *Determination
of the status of other cellular components
- Determination
of the status of the extracellular matrix (ECM)
- Is
significant systemic amyloidosis present?
- Are
significant advanced glycation end products
(AGEs) present? If so, which?
- What
is the occurrence of harmful molecules secreted by senescent cells in the
ECM, such as matrix metalloproteinase-3?
- Have
other alterations of the ECM occurred?
- Determination
of the extent of amyloid b
deposits and tau tangles in the brain
- Investigation
of prion protein (PrP)
- Investigation
of potentially subclinical prion diseases
- 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
- Determine
if tissues contain PrP-positive protein
accumulations or deposits
- *Investigation
of the degree of immunosenescence
- Determination
of whether immunosenescence is general or clonal for particular pathogens
- What are the relative proportions of
naive and memory T cells and B cells?
- Determination of the count of T cell
receptor rearrangement
excision circles, a biomarker of immunological aging
- What is the status of the thymus?
- What is the production of IL-7 in the
thymus?
- What is the production of IL-7 in bone
marrow stromal cells?
- What is the expression of CD28 for CD8
T cells?
- What is the fraction of replicatively
senescent T cells and B cells?
- Determination
of CD4:CD8 ratio
- Determination
of CMV status and other sources of chronic antigenic stimulation
- Identification
of dysfunctional CD8 cells by presence of double positive KLRG-1 and CD57.
- Investigation
of atherosclerosis
- Investigation
of macular degeneration
- *Investigation
of hormones
- Determination
of the ability of pituitary cells to express growth hormone
- Determination
of the ability of various cell types to express IGF-1
- Determination
of the functionality of growth hormone and IGF-1 receptors
- Investigate
secretion of other hormones and their receptors
- Corpora
amylacea
- Determine
the number, location, and size of corpora amylacea in the central nervous
system and compare with other age groups
- Correlate
the occurrence of corpora amylacea with the deposits of other misfolded
proteins
- Determine
the protein content of corpora amylacea
- Analysis
of proteasome activities
- Analysis
of accumulated data
- Meta-analysis
of existing studies
- Protection
of the privacy of subjects
C. Procedures for Intervention
in Aging
- Determine
methods for reversing sarcopenia
- Identify
factors in serum of young mice that activate muscle satellite cells in
old mice to repair injured muscles
- Determine
if injection of identified factors into old mice enhance repair of
injured muscles
- Determine
cellular source of identified factors in young mice
- Determine
cause of failure of cells in old mice to secrete the identified factors
- Identify
molecular signals emitted by injured muscles in mice
- Determine
if injection of signals simulating muscle injury plus factors that
activate muscle satellite cells can reduce the effects of sarcopenia in aged mice
- Determine
if human factors equivalent to those identified in mice can reverse the
effects of sarcopenia in human muscle tissue in
vitro
- Conduct
clinical trials in supercentenarians of effects
of sarcopenia reversing factors
- Determine
effects of sarcopenia reversing factors on cell
types other than muscle satellite cells
