X-Message-Number: 13260
From: Eugene Leitl <>
Date: Tue, 15 Feb 2000 18:56:12 -0800 (PST)

ripped from SCIENCE-WEEK February 18, 2000

Concerning the application of science to the extension of human
life span, there are three considerations: a) improved public
hygiene and public health measures important in the prevention of
disease; b) improved treatment of fatal diseases that appear in
middle and old age; c) actual retardation of the biological aging
process. With respect to the first two, there has been
considerable progress, particularly during the past 100 years;
with respect to the third, there has been no real progress at all
in terms of results, but our understanding of the biological
aging process has significantly improved during the past few
... ... Michael R. Rose (University of California Irvine)
presents a review of current ideas concerning the biological
aging process, the author making the following points:
     1) The author points out that all attempts to restore or
sustain youthful vigor in humans have failed to achieve their
goal. Individuals who currently survive past 65 years of age are
only slightly more likely to enjoy a robust old age than their
counterparts 2000 years ago. Although life expectancy has
increased during the past century due to advances in medical
therapy and sanitation systems, nothing slows the innate
processes that cause adults to age and suffer a decline in
physiological functioning as they grow older. Successful
treatment of one illness late in life often means that another
illness takes its place. "Infirmity remains the lot of those
older than 80, however much the media may dote on the 90-year old
marathon runner."
     2) The author states that the current view among
evolutionary biologists is that weakened natural selection allows
deleterious late-acting genes to spread in a population.
Calculations indicate that the force of natural selection on
survival in sexually reproducing populations drops soon after the
earliest age of reproduction is reached. Aging has evolved
because genes that produce deleterious effects late in life meet
little or no opposition from natural selection, and thus become
rampant in the gene pool. [Editor's note: Contrast with this the
approach of molecular biologists evident in the relevant
background material below.]
     3) In the 1940s and 1950s, J.B.S. Haldane (1892-1964) and
P.B. Medawar (1915-1987) were the first to introduce this
evolutionary explanation of aging. W.D. Hamilton and B.
Charlesworth then made the thesis mathematically rigorous in the
1960s and 1970s. Hamilton and Charlesworth established that for
sexually reproducing organisms (i.e., organisms that do not
reproduce by splitting in two), the force of natural selection on
survival falls with adult age and then disappears entirely late
in life. Since natural selection is the source of all adaptation,
and thus of health, the hardiness of the population of older
organisms declines as natural selection fades out. Eventually,
with the continued absence of natural selection at later ages,
survival may be so imperiled that optimal conditions and medical
care may be unable to keep the older individual alive.
     4) Evolutionary theory and some crude experiments suggest
that hundreds of genetically determined biochemical pathways
influence longevity and might thus be manipulated to postpone
aging. So far, however, only a handful of genes that could be
involved have been discovered, principally in the unsegmented
roundworm (nematode) Caenorhabditis elegans and in the fruit fly
Drosophila melanogaster. Whether results in these organisms apply
to humans remains to be determined.
     5) Among the potential human longevity therapies that have
been publicized in recent years are exercise, diet restriction,
and delivery of various substances such as growth hormone, the
enzyme telomerase, and anti-oxidants. Exercise has not been shown
to increase long-term survival; diet restriction has not been
studied systematically in humans; increasing hormone levels is
potentially dangerous; telomerase experiments have not
demonstrated an increase in longevity in any living organism;
there is no research demonstrating a longevity-producing anti-
oxidant effect in humans, or even research demonstrating a safe
method for blocking the production of free radicals or removing
free radicals once produced. [Editor's note: There is no direct
evidence that the ingestion of so-called "anti-oxidant" foods
results in the block or removal of free radicals in human
tissues. There is some evidence, however, that the ingestion of
certain anti-oxidant substances (e.g., ascorbic acid, vitamin E,
beta-carotene) may reduce the risk of human coronary artery
Michael R. Rose: Can human aging be postponed?
(Scientific American December 1999)
QY: Michael R. Rose, Univ. of California Irvine, 714-856-6703
Summary by SCIENCE-WEEK [http://scienceweek.com] 18Feb00
[For more information: http://scienceweek.com/search/search.htm]
Related Background:
Most multicellular organisms exhibit a progressive and
irreversible physiological decline that characterizes what is
called "senescence" -- the aging process. The molecular basis of
this process is unknown, but various mechanisms have been
postulated, including: a) cumulative damage to DNA leading to
genome instability; b) biochemical pathway alterations that lead
to changes in *gene expression patterns; c) *telomere shortening
in replicative cells; d) oxidative damage to critical
macromolecules by reactive oxygen species; and e) nonenzymatic
*glycation of proteins. Experimental genetic manipulation of the
aging process in multicellular organisms has been achieved in the
fruit fly Drosophila through the overexpression of certain
enzymes, and in the nematode worm C. elegans through alterations
in the *insulin receptor pathway, and in both organisms through
the experimental selection of stress-resistant mutants. In
mammals, however, the only intervention that appears to slow the
intrinsic rate of aging is caloric restriction. Most studies of
caloric restriction in mammals have involved laboratory rodents
subjected to a long-term 25 to 50 percent reduction in caloric
intake without essential nutrient deficiency, and the result in
these rodents is a delayed onset of age-associated pathological
and physiological changes and an extension of maximum lifespan.
Various mechanisms have been postulated to explain this result,
including increased DNA repair capacity, altered gene expression,
depressed metabolic rate, and reduced oxidative stress.
... ... C-K. Lee et al (4 authors at University of Wisconsin, US)
now present a study to examine the molecular events associated
with aging in mammals, with experiments involving analysis of the
aging process in *skeletal muscle of mice. The authors report
that the use of high-density *oligonucleotide arrays representing
6347 genes (5 to 10 percent of the mouse genome) revealed that
aging resulted in a differential gene expression pattern
indicative of a marked stress response and lower expression of
metabolic and biosynthetic genes. Most alterations were either
completely or partially prevented by caloric restriction.
*Transcriptional patterns of calorie-restricted animals suggest
that caloric restriction retards the aging process by causing a
metabolic shift toward increased protein turnover and decreased
macromolecular damage. The authors state: "The data presented
here provide the first global assessment of the aging process in
mammals at the molecular level and underscore the utility of
large-scale parallel gene expression analysis in the study of
complex biological phenomena."
C-K. Lee et al: Gene expression profile of aging and its
retardation by caloric restriction.
(Science 27 Aug 99 285:1390)
QY: Tomas A. Prolla []
Text Notes:
... ... *gene expression patterns: This refers to the profile of
genes in a genome that are actually operating (i.e., undergoing
expression) at any point in time. In a mammal, for example, a
liver cell is a liver cell because of a particular profile of
expressed genes, and what that liver cell is doing at any point
in time is determined by variations of that profile. It is the
operating patterns (gene expression patterns) of the genome that
are the paramount determinants of the behavior of cells.
... ... *telomere: Telomeres are defined ends of chromosomes
that contain specific repeated DNA sequences. They are essential
for normal chromosome replication, and since their length
shortens a bit with each replication, they are believed to be
involved in the aging of the cell.
... ... *glycation of proteins: "Glycation" is the post-
translational (i.e., after protein synthesis) modification of a
protein by the covalent attachment of a sugar residue, the
modification resulting from a spontaneous amino-carbonyl reaction
("Maillard reaction"). Glycation of various proteins has recently
been implicated in the etiology of various diseases such as the
development of Alzheimer's-type pathologies (e.g., dementias).
... ... *insulin receptor pathway: Insulin is a polypeptide
chemical messenger (hormone) comprising 51 amino acids in two
chains linked by disulphide bridges. The insulin receptor is a
specific membrane protein derived from an intracellular precursor
and transported from specialized intracellular structures to the
cell surface.
... ... *skeletal muscle: In general, the term "skeletal muscle"
refers to striated muscle fibers (singly or in a collection)
attached at one or both ends of a part of the body skeleton.
"Striated muscle" is muscle usually associated with voluntary
motion, the adjective "striated" arising from the microscopically
visible cross striations which occur in the fibers as a result of
regular overlapping of thick and thin muscle fiber filaments
(myofilaments). In general, such fibers are specialized for rapid
contraction and relaxation.
... ... *oligonucleotide arrays: The essential idea concerning
the use of "arrays" in determining gene expression patterns
involves the fact that for every gene (DNA sequence) undergoing
expression there exists in the cytoplasm a specific RNA whose
nucleotide sequence is a result of transcription of that gene
(see next note on "transcriptional patterns"). There exists now a
technique for profiling the large variety of RNAs that can be
extracted from tissue, the technique depending on highly ordered
arrays of large numbers of oligonucleotide probes (essentially
pieces of DNA) in a parallel format, with specific DNA-RNA
interactions producing localized fluorescences, and the array of
fluorescences providing a profile of detectable RNAs. A
determination of the profile of existing RNA sequences implies
the profile of the DNA sequences (genes) that are being naturally
expressed in the genome, and if one knows which genes are
involved with which functions in that particular cell or
organism, one has obtained a profile of existing functions. The
use of such arrays of nucleotide probes (sometimes called micro-
arrays or "chips") is now highly automated ("robotic"), and the
technique can be used to determine the expression profile of
thousands of genes in an ensemble of cells.
... ... *Transcriptional patterns: "Transcription" is the process
by which genetic information in DNA is converted into RNA.
Summary & Notes by SCIENCE-WEEK [http://scienceweek.com] 24Sep99
Related Background:
Our knowledge of the basis of senescence of cells, tissues, and
organisms (including humans) has entered a new phase in recent
decades because of the new vistas opened by molecular biology.
Model systems have started to provide insights, and one important
approach has been the identification of genes that determine the
lifespan of an organism. The very existence of genes that when
mutated can extend lifespan suggests to many researchers that one
or a few processes may be critical in aging, and that a slowing
of these processes may slow aging itself. ... ... In a short
review of current research in the molecular biology of aging and
lifespan, L. Guarente et al make the following points: 1) In the
budding yeast Saccharomyces cerevisiae, aging results from the
asymmetry of cell division, which produces a large mother cell
and a small daughter cell arising from the bud. Much of the
macromolecular composition of the daughter cell is newly
synthesized, whereas the composition of the mother cell grows
older with each cell division. It has been shown that mother
cells of this yeast species divide a relatively fixed number of
times, and exhibit a slowing of the cell cycle, cell enlargement,
and sterility. Analysis of *ribosomal DNA in old cells reveals an
accumulation of *extrachromosomal ribosomal DNA of discrete
sizes, apparently representing a cumulative fragmentation of
chromosomal ribosomal DNA. The authors suggest it will be of
great interest to assess the generality of this process as an
aging mechanism. 2) In *Caenorhabditis elegans (a *nematode worm;
see notes), the *neurosecretory system regulates whether animals
enter the reproductive life cycle or arrest development at a
primitive *diapause stage. Developmental arrest is apparently
induced by a *pheromone and involves behavioral and morphological
changes in many tissues of the animal, with the lifespan becoming
4 to 8 times longer than that of the normal 3-week lifespan of
fully developed animals. Declines in pheromone concentration
induce recovery to reproductive adults with normal metabolism and
lifespan. Genes that regulate the function of the C. elegans
diapause and the neuroendocrine aging pathway have been
identified, and at least one of these genes codes for an
*insulin-like receptor apparently involved in metabolism. The
authors suggest that if the association of longevity and diapause
is general, it is possible that *polymorphisms in the human
insulin receptor-signaling pathway genes and related gene
*homologues may underlie genetic variation in human longevity. 3)
In plants, there is a large range of lifespans in the various
plant kingdoms. Certain tree species live for well over a
century, whereas other plants complete their life cycle in a few
weeks. The "yellowing" of leaves is often referred to in the
plant literature as leaf senescence or the "senescence syndrome"
-- referring to the process by which nutrients are mobilized from
the dying leaf to other parts of the plant to support their
growth. The senescence syndrome is characterized by distinct
cellular and molecular changes, with the chloroplast the first
part of the cell to undergo disassembly (producing the
"yellowing"). In many plant species, certain hormones can either
enhance or delay senescence. Although the genes that are
expressed during the plant senescence syndrome (as well as ways
to manipulate such senescence) have been identified, much remains
to be done to understand the molecular basis of aging in plants.
For example, nothing is known about the signal transduction
pathways that lead to altered gene expression during senescence,
or how plant hormones such as *cytokinin influence senescence.
But there are now many tools to explore this process. The authors
conclude: "It remains to be seen whether common mechanisms link
the aging process in diverse organisms."
L. Guarente et al (3 authors at 3 installations, US)
Aging, lifespan, and senescence.
(Proc. Natl. Acad. Sci. US 15 Sep 98 95:11034)
QY: Leonard Guarente, Mass. Inst. of Technology 617-253-1000.
Text Notes:
... ... *ribosomal DNA: A ribosome (not to be confused with
riboZYME) is a small particle, a complex of various ribonucleic
acid component subunits and proteins that functions as the site
of protein synthesis. The term "ribosomal DNA" refers to the gene
or genes that code for the RNA in ribosomes. In other words, the
term "ribosomal DNA" does not refer to any DNA in ribosomes
(there is no DNA in ribosomes).
... ... *extrachromosomal: In general, this refers to anything
outside of chromosomes, and in this case to DNA fragments
unincorporated into chromosomal DNA.
... ... *Caenorhabditis elegans: This is a small (1 mm) nematode
worm. It is transparent, hermaphroditic, free-living, and found
in soil. It has a relatively small genome (approximately 19,000
genes), and only a few types of cells in its body. It has a 16-hr
embryogenesis that can be achieved in a petri dish, and is thus
highly suitable for the study of developmental and behavioral
... ... *nematode: An abundant and ubiquitous phylum of
unsegmented roundworms.
... ... *neurosecretory system: In general, all neural systems
contain both neurons that themselves secrete chemical messengers
and neurons that signal special secretory cells to secrete
chemical messengers. A neurosecretory pathway is a delineated
signaling system that involves such a resultant secretion.
... ... *diapause: In general, this refers to any programmed
period of suspended development in invertebrates. 
... ... *pheromone: In general, a chemical substance which, when
released into an animal's surroundings, influences the
development or behavior of other individuals of the same species.
... ... *insulin: A protein hormone that promotes uptake by body
cells of free glucose and/or amino acids, depending on target
cell type.
... ... *polymorphisms: A genetic polymorphism is a naturally
occurring variation in the normal nucleotide sequence of the
genome within individuals in a population. Variations are denoted
as polymorphisms only if they cannot be accounted for by
recurrent mutation and occur with a frequency of at least about 1
... ... *homologues: In general, the term "homologous" means
having the same structure. But the term has special uses in
genetics and evolution biology.
... ... *cytokinin: A group of plant growth substances. They are
chemically identified as derivatives of the purine base adenine.
They stimulate cell division and determine the course of
differentiation. They work synergistically with other plant
hormones called "auxins".
Summary & Notes by SCIENCE-WEEK [http://scienceweek.com] 6Nov98

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