The 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.

Genetic Techniques to Enhance Vitality in Older Patients

The 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 they come.

The 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.

Vitality 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.

Strehler [1] 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 [2]. 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 Werner syndrome.

My 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.

With 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.

With 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 [5].

On 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.

To 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 temporary.

This 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.

SUMMARY: 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.

REFERENCES:

1. 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 Dec;11(5-6):379-82.      

2. 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 Dec 20;92(2-3):101-9.

3. Johnson FB, Sinclair DA, Guarente L: Molecular biology of aging. Cell 1999 Jan 22;96:291-302.

4. Rothstein R, Gangloff S: The shuffling of a mortal coil. Nature Genetics 1999 May;22:4-6.

5. Tondravi MM, Yao MC: Transformation of Tetrahymena thermophila by microinjection of ribosomal RNA genes. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4369-73.

Richard P. Huemer, M.D.

June 15, 2003