X-Message-Number: 14954
From: <>
Date: Sun, 19 Nov 2000 16:12:27 +0100 (CET)
Subject: ON FOOD RESTRICTION AND AGING

(((ripped from the excellent SCIENCE-WEEK November 17, 2000, I recommend
a subscription)))

[...]

2. BIOLOGY OF AGING:
ON FOOD RESTRICTION AND AGING
Yeast undergo only a finite number of divisions, after which the
yeast cells die; thus, the life-span in yeast is defined by the
number of divisions each cell completes. Researchers have now
induced caloric restriction in yeast by limiting glucose
availability or by genetically crippling the ability of yeast to
sense and respond to glucose. Caloric restriction extended yeast
longevity by 20 to 40 percent, similar to the relative life-span
extension induced by caloric restriction in mammals. This
extension was not observed in yeast strains mutant for the gene
SIR2 (which encodes the silencing protein SIR2p) or the gene NPT1
(a gene in a pathway in the synthesis of the oxidized form of
nicotinamide-adenine dinucleotide (NAD). These results may link
caloric restriction to the control of gene expression and to the
suppression of DNA damage (loss or rearrangement of DNA) caused
by mitotic recombination. (Science 22 Sep 00 289:2126)

[...]

2. BIOLOGY OF AGING:
ON FOOD RESTRICTION AND AGING
During the past decade, an important change has occurred in the
thrust of aging research. For the first time, we have the results
of a wide variety of systematic experiments in molecular biology
and biochemical cell physiology related to questions concerning
senescence in various organisms ranging from the most primitive
to the most complex, and researchers who work in this field are
more hopeful than ever before that important breakthroughs will
occur in the near future.
... ... S-J. Lin et al (3 authors at Massachusetts Institute of
Technology, US) now report that in a study involving mimicking of
caloric restriction in yeast by physiological or genetic means,
they found a substantial extension in life span. This extension
was not observed in yeast strains mutant for the gene SIR2 (which
encodes the *silencing protein SIR2p) or the gene NPT1 (a gene in
a pathway in the synthesis of the oxidized form of *nicotinamide-
adenine dinucleotide (NAD). The authors suggest their findings
indicate that the increased longevity induced by caloric
restriction requires the activation of SIR2p by NAD.
... ... In a commentary on this work, Judith Campisi (Lawrence
Berkeley National Laboratory, US) makes the following points:
     1) Current hypotheses concerning the cause of aging
generally fall into one or two categories: a) the involvement of
extrinsic or intrinsic factors that damage intracellular or
extracellular molecules; b) changes in *gene expression that are
either programmed or that are brought about by nonmutational
changes in DNA structure. To what extent these hypotheses overlap
or intersect is not known.
     2) Regardless of the hypothesis, however, caloric
restriction has been an important tool for testing ideas about
causes of aging in animals. Caloric restriction -- reducing the
food intake of animals by 50 to 70 percent -- reliably extends
the mean and maximum life-spans of several species, including
mammals. Caloric restriction postpones most age-related pathology
and alters many, but not all, age-related processes. It is
thought to do this primarily by reducing oxidative stress and
damage caused by reactive oxygen species. Yet despite more than
half a decade of research, the major pathway through which
caloric restriction acts remains enigmatic. Now S-J. Lin et al
describe intriguing results that may link caloric restriction to
the control of gene expression and to the suppression of DNA
damage (loss or rearrangement of DNA) caused by *mitotic
recombination.
     3) Yeast undergo only a finite number of divisions, after
which the yeast cells die; thus, the life-span in yeast is
defined by the number of divisions each cell completes. Lin et al
induced caloric restriction in yeast by limiting glucose
availability or by genetically crippling the ability of yeast to
sense and respond to glucose. Caloric restriction extended yeast
longevity by 20 to 40 percent, similar to the relative life-span
extension induced by caloric restriction in mammals.
     4) The author (Campisi) points out that a fundamental
difference between adult mammals and model organisms such as the
yeast, the *nematode, and the fruit fly is the prevalence of
cancer in mammals, and essentially the lack of cancer in yeast,
worms, and flies. In mammals, mutations, probably coupled to the
changes in cellular function that accompany aging, give rise to
cancer, which poses an additional threat to longevity. In
addition, most human cells undergo *telomere attrition with
successive cell divisions and aging (i.e., the ends of
chromosomes become progressively shorter. The extent to which
telomere-induced cellular senescence contributes to human aging
is not yet clear.
-----------
S-J. Lin et al: Requirement of NAD and _SIR2_ for life-span
extension by caloric restriction in Saccharomyces cerevisiae.
(Science 22 Sep 00 289:2126)
QY: Leonard Guarente: 
-----------
Judith Campisi: Aging, chromatin, and food restriction --
connecting the dots.
(Science 22 Sep 00 289:2062)
QY: Judith Campisi: 
-----------
Text Notes:
... ... *silencing protein: In general, a protein factor that
negatively controls (i.e., inhibits) expression of a specific
gene or genes.
... ... *nicotinamide-adenine dinucleotide (NAD): An important
coenzyme in *electron transfer reactions in biological cells, in
particular in oxidative reactions in *aerobic respiration.
... ... *electron transfer: (electron transport) This refers to a
sequence of steps in the final stage of the aerobic respiration
biochemical pathway in which high energy electrons are
effectively passed through a series of membrane-bound carrier
molecules to support a proton gradient involved in energy
storage. The term "transport" here  refers essentially to a
chemical flow diagram and not necessarily to an actual spatial
translocation of electrons.
... ... *aerobic respiration: In general, the direct utilization
of oxygen by a biological system.
... ... *gene expression: In general, the term "gene expression"
includes any gene activity, but particularly an activity that
produces the synthesis or activation of a specific protein.
... ... *mitotic recombination: In general, the term 
"recombination" refers to the integration of DNA fragments
into a particular site in a genome, sometimes with the formation
of new advantageous or deleterious genes. "Mitotic recombination"
refers to recombination that occurs during cell division. 
... ... *nematode: An abundant and ubiquitous phylum of
unsegmented roundworms.
... ... *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.
-------------------
Summary & Notes by SCIENCE-WEEK http://scienceweek.com 17Nov00
For more information: http://scienceweek.com/swfr.htm
-------------------
Related Background:
BIOLOGY OF AGING: CALORIC RESTRICTION AND GENE EXPRESSION
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
For more information: http://scienceweek.com/swfr.htm

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