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Is the secret to a long life "all in the genes?"

The Gene

    Scientists at Beth Israel Deaconess Medical Center and Division on Aging (in cooperation with Harvard Medical School ) in Boston, MA have recently identified a gene or set of genes that may drastically affect the way a person ages.  The function of this "longevity gene" is not known, but scientists are hoping to learn more from this gene about the way that individual cells "age," and eventually die.

The Popular Press

    This story appeared in USA Today on August 27, 2001 ( read the story ).  The article is very well put-together from a scientific point of view.  It states that "a group of genes within a region of chromosome 4 may hold the secret to very, very long life"  (, 8/27/01).  The article is very accurate in its description of both the gene and the methods that the scientists at Beth Israel Deaconess Medical Center used to obtain and interpret data.  The article does not effectively make clear exactly how new this development is.  This gene has not been studied much at all, and very little is known about its function.  While brief and written for a layperson audience, this article does achieve its objective - to show the continually widening scope that genetics and genomics encompass.

The Science Behind The Gene

   The article that appears in USA Today states that "the study will be published Tuesday in the Proceedings of the National Academy of Sciences ." (read the story )  The PNAS article is the official paper that was published by the researchers in Boston.  It is aimed toward an audience proficient in cellular biology, and is much more detailed in its description of the methods, analysis of data, and results obtained from this research.  The basic premise for the study is the link between certain unknown genes and an "ability to age well and achieve exceptional longevity" (Puca, Annabale, et al., 2001).  Thus, the study began with a minimum age for candidates of 100 years.  However, in order to achieve a large enough sample size, the minimum age for the main candidates was lowered to 98 years.  Once these candidates of 98+ years were identified, their family history was searched in order to obtain at least one sibling with another minimum age requirement (males > 91 years, females > 95 years of age).  These groups having candidates matching all requirements were dubbed "sibships."  There were 137 sibships and 303 individuals participating in the study.  Blood was drawn from each candidate in each sibship, and was examined for similar loci throughout the entire genome.  This was done by attaching 400 markers throughout the genome, with an average "marker density of 10 centimorgans" (Puca, Annabale, et al., 2001).  The data returned in a form shown in figure 1 (below, borrowed from PNAS, 2001).  The line graph can be loosely interpreted as the frequency with which a certain marker was present in the participants in the study.  The Y-axis contains the MLS (or Maximum Logarithm of odds Score) for the markers, while the X-axis shows the number of centimorgans (location) of each marker on the individual chromosomes.  An MLS of 2.0 was chosen as the maximum MLS for which the number of matches for one loci would be accounted for by chance alone.  Therefore, if a certain marker exceeded an MLS of 2.0, it could be said that this was not a random coincidence, and is scientifically significant.  Notice below that near the D4S1572 marker on chromosome 4, the MLS exceeds 2.0, whereas on chromosome 5, there is not one locus that shows significant correlation.  The region near the D4S1572 marker was finely mapped, showing later that the marker with the highest MLS was the D4S1564 marker, with an MLS of 3.65.

        Figure 1.
Chromosome 4 and 5 LOD scores *permission to use image requested
                                                                                                                                                                                      from Proceedings of the National Academy of Sciences .

    Table 1 (below) shows the results of the fine mapping around the D4S1572 marker, with the position of the marker tested, the MLS, and the maximum Heterogeneity Logarithm of Odds (hlod) scores shown for each marker.  The hlod test is very similar to the test that yields an MLS, and the scores may be evaluated in a similar manner.  In Table 1, the MLS and hlod scores both peak at the D4S1564 marker, identifying this marker as the locus of maximum correlation.

       Table 1.   Nonparametric MLS and parametric hlod scores within the exceptional longevity susceptibility locus relative to
        markers in the chromosome 4 region
           Marker                Position              MLS*           hlod* dom
            D4S1534                    95.0                0.57                0.54
            D4S414                    100.8                1.53                1.30
            D4S2986                  105.3                2.78                2.26
            D4S1572                  108.0                3.07                2.57
            D4S411                    109.0                3.07                2.60
            D4S1564                  112.6                3.65                3.26
            D4S406                    117.1                2.55                2.15
            D4S1611                  121.6                1.70                1.56
            D4S402                    124.5                1.39                1.06
            D4S2975                  126.7                0.94                0.89
        * Nonparametric MLS and parametric hlod scores were calculated for within the exceptional longevity susceptibility
        locus relative to markers in the chromosome 4 region. Positions are from the Marshfield map . Fine mapping at
        an average of 1 marker every 3 cM around the peak noted in Fig. 1 resulted in an increased MLS (3.65) at
        marker D4S1564. A dropoff of 1.5 in the MLS score on either side of the peak MLS defines the area in which we can
        be 95% confident the gene resides. A dropoff in the MLS of 2 on either side of the peak is observed in a 20-cM
        region encompassed by D4S414 and D4S1611. The MLS scores in this region and the hlod scores under the
        dominant model are shown.
                                                                                                 *all data in blue borrowed from Proceedings of the National Academy of Sciences , permission requested.

The data for the D4S1564 marker is shown below:

LOCUS       HS248ZG9      331 bp    DNA             PRI       28-NOV-1994
DEFINITION  H. sapiens (D4S1564) DNA segment containing (CA) repeat; clone
            AFM248zg9; single read.
VERSION     Z23817.1  GI:394017
KEYWORDS    CA repeat; dinucleotide repeat; GT repeat; microsatellite DNA;
            microsatellite marker; repeat polymorphism.
SOURCE      human.
  ORGANISM  Homo sapiens
            Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
            Mammalia; Eutheria; Primates; Catarrhini; Hominidae; Homo.
REFERENCE   1  (bases 1 to 331)
  AUTHORS   Weissenbach,J.
  TITLE     Direct Submission
  JOURNAL   Submitted (12-JUL-1993) Genethon, B.P. 60, 91002 Evry Cedex France.
REFERENCE   2  (bases 1 to 331)
  AUTHORS   Gyapay,G., Morissette,J., Vignal,A., Dib,C., Fizames,C.,
            Millasseau,P., Marc,S., Bernardi,G., Lathrop,M. and Weissenbach,J.
  TITLE     The 1993-94 Genethon human genetic linkage map
  JOURNAL   Nat. Genet. 7 (2 Spec No), 246-339 (1994)
  MEDLINE   95004593
COMMENT     cloning vector is M13mp18ASBB;
            full automatic.
FEATURES             Location/Qualifiers
     source          1..331
                     /organism="Homo sapiens"
                     /cell_line="CEPH 134702"
                     /clone_lib="genomic DNA"
BASE COUNT       92 a     81 c     49 g     99 t     10 others
        1 agctactnag naggctgggg caggaaanta anttcagccc aggaggtgaa ggttgcagtn
       61 agccgagatc acgccactgc actccagcct gggcaacana ntganacacc tctttctttn
      121 tntctctctc tctctctctc tctttcacac acacacacac acacacacac acaatgaaaa
      181 aaagtcattt tcctatagaa tgctctccag ttactgataa agaatactcc cctttctcaa
      241 tgtttcctag aaatctcatt tgagtttaac aaagttcaat ttaagaagtt tgatcacatt
      301 taatgttttt atttcctttg ccacggtttt t
                                                                                                    *data in purple borrowed from BLAST search on National Center for Biotechnology Information
                                                                                                    database online, results from Genbank.  Permission requested to use this data.


    This study is an important study, but is just the beginning of the study of the relationship between genetics, genomics, proteomics, bioinformatics, and aging.  More studies need to be conducted to further understand the cellular and genetic pathways that are involved in aging.  The genes that assist cells and organisms in aging must be understood, and then the proteins that these genes encode must be studied.  Clearly there is a long way to go in this study, but there are many areas that this type of study may help us to understand.  For example, the study may show us the mechanisms behind aging in cells, death in cells, or aging and death in organisms.  Many age-related diseases may be more fully understood with the information from the continuation of this study as well.  Cancer, Alzheimer's disease, and many other diseases may finally be explained and cured from information obtained from a genomic point of view.  The study of aging and its genetic/genomic components may open a Pandora's box of moral issues, however.  If a group of researchers find a mechanism to slow or stop aging in cells, it may be possible for them to find a "cure" for death.  However, if done correctly and morally, this type of study could be a very important tool for years to come.

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