Bill and Melinda Gates Foundation asked for ideas to help meet global health
challenges. On July 29, 2003, the website www.grandchallengesgh.org
noted that that "the Call for Ideas has now been completed."
They commented: "We are gratified by
the magnitude of the response, which resulted in over 1,000 submissions from
dozens of countries on all continents." This is the idea WE submitted.
Techniques to Enhance Vitality in Older Patients
mean age of the populations in developed countries is increasing. Aging is
accompanied by increased likelihood of disease, greater difficulty in treating
disease, and increased costs for all types of medical care. In the United
States, Medicare expenditures for senior citizens will burgeon as the
baby-boom generation ages, to the point that (a) expenditures for medical care
will exceed any other category of Federal spending, (b) the Medicare system
will become bankrupt, (c) Medicare services will be severely curtailed, or (d)
some combination of these events will occur. It would be highly desirable to
postpone healthcare expenses as long as possible, and to minimize them when
survival of an individual depends upon the balance between two forces: the
external force of mortality, and the internal force of vitality. The latter
declines exponentially with age, so that morbidity and mortality increase with
age; in human populations, mortality will double over any eight-year span.
Enhancing vitality in older individuals would reduce healthcare costs both by
postponing them and by reducing time in hospital.
in the context of this proposal means the body's ability to synthesize useful
proteins, including antibodies, enzymes, and structural proteins. Protein
synthesis depends in turn upon the integrity and functionality of the
ribosomes that translate coded genetic information into protein molecules. A
necessary component of ribosomes is ribosomal RNA, without which they cannot
function. Ribosomal RNA is specified by tandemly-repeated genes (rDNA), of
which young cells possess multiple copies.
 demonstrated that hybridizable rDNA in human and canine postmitotic cells
dwindles away with age at a species-specific rate. Decline of rDNA gene
activity is also demonstrable as loss of stainable nucleolar organizing
regions in dividing human cells . Instability of rDNA is responsible for
the aging of yeast cells [3,4], in which the mechanism has been well studied.
Interestingly, a yeast gene relevant to the process will, if deleted, shorten
lifespan, and that gene is a homolog of the human gene that is defective in
proposal is that resistance to disease could be enhanced, perhaps approaching
youthful levels, by means of increasing the rDNA in cells. At present, it is
not known how to accomplish this. Two possible techniques come to mind: (1)
activating those genes that normally increase the copy-number of rDNA under
physiologic conditions, or (2) inserting externally-produced copies of rDNA
into cells by means of a viral vector.
regard to (1), during meiotic division to form sex cells a genetic subroutine
is activated that greatly increases copy-number of rDNA; oocytes can contain
many thousands of copies. If the subroutine could be characterized
sufficiently well, it might be possible to recall it at will by derepressing
the relevant genes in the correct sequence.
regard to alternative (2), it might be possible temporarily to introduce
exogenous rDNA into cells by means of a viral vector, perhaps a retrovirus. It
is actually possible to transplant functional rDNA into one-celled organisms,
achieving a stable transformation, by means of microinjection of rDNA into the
organism's macronucleus .
the basis of yeast studies, one supposes that other strategies might be
possible, perhaps involving inactivation of the Fob1p protein or
overexpression of topoisomerase. It would depend on the degree of relevance of
the yeast studies to the human situation.
forestall any objections that genetic enhancement of vitality might
undesirably extend lifespan, with its attendant social costs, I point out that
lifespan is limited by a number of determinants, such as lipid peroxidation,
glycation and cross-linking of molecules, racemization of amino acids,
mitochondrial-DNA mutations, etc., none of which is obviously linked to rDNA
loss. Moreover, the techniques outlined here are intended to aid in treating
the sick, not the elderly population in general, and their effects should be
proposal would not immediately impact the developing world, but it will in the
future. The now-youthful population of the developing world will age, and thus
progressively burden governmental resources, just as those in the developed
world are already being burdened. The pace of third-world development would
then be slowed, unless it became possible to mitigate and postpone healthcare
expenses of an expanding elderly population.
Diminished vitality is defined as loss of protein-synthesizing capacity,
arising from instability of the tandemly-duplicated genes (rDNA) that specify
ribosomal RNA. It is proposed either to artificially activate the natural
genetic mechanisms that increase rDNA copy-number, or to introduce exogenous
rDNA into cells by means of a viral vector, for the purpose of temporarily
restoring vitality to elderly patients. Restoring vitality would diminish and
postpone burgeoning healthcare costs that all nations, now and in the future,
will otherwise face as their populations age.
Strehler BL, Chang MP: Loss of hybridizable ribosomal DNA from human
post-mitotic tissues during aging: II. Age-dependent loss in human cerebral
cortex--hippocampal and somatosensory cortex comparison. Mech Ageing Dev 1979
Thomas S, Mukherjee AB: A longitudinal study of human age-related ribosomal
RNA gene activity as detected by silver-stained NORs. Mech Ageing Dev. 1996
Johnson FB, Sinclair DA, Guarente L: Molecular biology of aging. Cell 1999 Jan
Rothstein R, Gangloff S: The shuffling of a mortal coil. Nature Genetics 1999
Tondravi MM, Yao MC: Transformation of Tetrahymena thermophila by
microinjection of ribosomal RNA genes. Proc Natl Acad Sci U S A. 1986
Richard P. Huemer, M.D.
June 15, 2003
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