X-Message-Number: 3277
Date: Sun, 16 Oct 1994 17:44:22 -0400 (EDT)
From: 
Subject: SCI.CRYONICS COMPREHENSIVE REVIEW OF AGEING

Date sent:  16-OCT-1994 17:41:22 
>Newsgroups: bionet.molbio.ageing
>
>
>
>Contents include:
>
>1.) brief descriptions of topics generally encompassed, in order to
>    indicate what's going on in general; and
>2.) a few references, reviews and/or recent publications regarding
>    topics in aging research.  All references should of course be taken
>    to include "and references therein".
>
>
>Thanks,
>
>-- Tim Hughes
>
>
>I.  Definition of Aging
>
>        A. Senescence - Senescence refers to intrinsic adverse changes
>                during aging in an organism.  Strictly this is
>                manifest as an increasing likelihood of death as
>a function of time, measured either from birth or from
>some developmental stage. [Also, strictly the term "senescence"
>       should be used instead of "aging" in this FAQ but I
>haven't bothered.]  Cell senescence refers
>             to the limited proliferative capacity of cultured
>somatic cells (see below).
>
>                1. Gompertz Curve:  A mathematical function called
>                      the "Gompertz curve" can be derived to describe

>                      expected mortality statistics for a population 
of10%organisms whose
>probability of death increases as a function
>of time.Many populations (including humans)
>                      demonstrate a survival curve which
>can be fit closely by a Gompertz curve.  A
>                      critical parameter in the Gompertz expression is
>the MRDT (mortalitay rate doubling time) which is
>              considered the index of how fast organisms in
>      the population senesce, and it has been suggested
>      that in scientific studies true slowing of the
>      aging process occurs only when the MRDT increases,
>      regardless of other aging parameters (i.e., mean,
>      mode, maximum lifespan).
>
>General references on the study of aging:
>Finch, C. E. 1991.  Longevity, Senescence, and the
>  Genome. Univ. Chicago Press.843 pages including
>  references.
>
>Martin, George R. et al.  1993.  Aging - Causes and  4
>
>  Defenses.  Annu. Rev. Med. 44:419-29.  A quick
>  overview, not entirely comprehensive but easy reading.
>
>Kirkwood, T.B.L. and Cremer, T.  Cytogerontology Since
>  1881:  A Reappraisal of August Weismann and a Review
>  of Modern Progress.  Human Genetics (1982) 60:101-121.
>  A historical review of aging theories and arguments.
>
>
>II.  Theories and evidence regarding the
> aging of multicellular organisms
>
>A. General Arguments.
>Population genetics [something I know little about]
>  argues that no genetic trait which is detrimental
>late in life would be selected for, so
>no genes can survive throughout a population whose
>sole function is to cause senescence.  The remaining
>possibilites are as follows:
>7
>
>1. Antagonistic Plieotropy: It is possible for genes
>      which are benefical or necessary in youth or in
>the short term to be detrimental in the long term.
>      An example is the cytochrome oxidase, a
>      metabolic enzyme [detoxifant, I think] which is
>      responsible for the initial step in transforming
>      a number of dietary compounds into mutagenic agents.
>References:
>Aeschbacher, H-U. and Turesky, R.J. (1991)
>                          Mammalian cell mutagenicity and metabolism of
>   heterocyclic aromatic amines.  Mutation
>  Research, 256:235-250.
>
>2. Longevity Assurance Genes: t is also possible
>      that genes which are designed to protect us
>      from detriment be finite in capacity, as no
>      selection may exist for alleles which protect
>      for longer than the lifetime.  [Example:
>      genes involved in DNA damage control in somatic
>tissues.]21
>
>
>B.  Disposable Soma Theory:  It has been suggested that
>the optimal allocation of energy for an organism
>which reproduces repeatedly is to invest no more
>energy in somatic maintenance than is necessary
>to ensure reproduction.  [The originaldea,
>I believe, referred primarily to DNA damage.]
>[Also, this argument seems unlikely to me to apply to
>humans.  My understanding is that we
>consume 40% of our resting energy on brain activity,
>and about 30% of all ATP generated on maintaining
>transmembrane potentials (from which many cellular processes
>are driven, I'm not sure how much of that is converted into
>work and how much is lost by diffusion)
>and maintain a fairly warm body temperature.  This
>suggests to me that
>energy conservation is not a significant selective
>advantage for mammals and humans in particular.]
>
>5
>
>C. Somatic Mutation Hypothesis.
>        DNA is inherently unstable and is susceptible to
>numerous modification and damaging agents. As
>genetic material it requires constant maintenance.
>One of the original ideas about the aging process
>is that the accumulation of somatic mutations throughout
>the lifespan is responsible for dysfunction of cells
>and consequently of organs and individuals.  This
>has fallen out of favor as a mechanism for aging since
>DNA damage would be expected to be fairly random, and
>aging is largely consistent over a population.
>
>2. free radicals:  Reactive oxygen species are produced
>      by mitochondria in oxidative phosphorylation, the
>      biochemical pathy that allows us to utilize oxygen
>      in energy production [conversion, rather].  Free
>      radical species can also be produced by ionozing
>      radiation.  Free radicals can modify/damage a wide
>range of cellular molecules including DNA, lipids
>and proteins (see below).9
>
>
>2. carcinogens and mutagens:
>
>3. cancer:
>
>4. mitochondrial DNA damage:  Mitochondria contain a
>      small genome which due to its proximity to
>      oxidative phosphorylation activity is more
>      susceptible to oxidation than the nuclear DNA.
>      Human mtDNA is 16.6 kb and encodes
>      a small portion of the peptides involved in
>oxidative phosphorylation and also the rRNAs and
>      tRNAs needed to translate these genes.  It has
>een observed that the mutation rate of mtDNA
>is higher than that of the nuclear DNA, and also
>that there is a decline in oxidative phosphorylation
>activity in some tissues with age.  Mitochondrial
>genetics is complex due to interaction with
>nuclear genes, predominant maternal inheritance,

>d the possibility that not all mitochondria in33a cell need to be genetically 
identical.Nonetheless
>      a number of genetic diseases are linked to mtDNA,
>and that mutations in nuclear genes
>      can adversely affect mtDNA and/or oxidative
>phosphorylation.
>      It has been proposed that accumulated mtDNA damage
>is a mechanism in aging, and that mitochondria with
>genomic deletions would be enriched due to a replicative
>advantage.  [As with anyheory involving genomic
>instability, one must reconcile the fact that
>babies are inevitably born young.  In this case
>the question is: how do babies escape getting mom's
>20-40 year old mitochondria?]
>  References:
>    Wallace, D.C. (1992) Mitochondrial Genetics: A
>      Paradigm for Aging and Degenerative Diseases?
>      Science 256:628-632 (May 1 1992).
>
>5. apoptosis:
>6
>
>D. Endocrine cascade
>
>
>
>E. Cell Senescence.
>A number of types of human cells will undergo
>less than about 100 divisions when cultured
>(grown in a dish or flask), at which point the cells
>adopt a distinctive appearance and will not
>divide any further.  As stimulus to divide in mammalian
>tissues consists mainly of signaling factors
>it has been argued that senescence is a
>tissue culture artifact due to improper or inadequate
>signaling or an adaptive tolerance to signals.
>In large enough sample sizes, however,
>an inverse correlation between number
>of divisions obtained and age of donor is
>observed, and there also exists a rough correlation between
>species lifespan and number of divisions obtained.
>Furthermore cells from individuals with Werner's9
>
>        syndrome (premature aging) have a reduced proliferative
>capacity.  It has been proposed that cell senescence
>occurs in vivo and could be
>responsible for loss of homeostasis in tissues
>        of the elderly.  Cells which senesce in culture include
>fibroblasts, lymphocytes, various epithelial cells,
>and adrenocortical cells.  Tumor cells do not
>senesce in culture and it has also been proposed
>that senescence acts as a tumor-contromechanism
>by providing an additional hurdle for growth-errant
>cells.  It is important to note that no direct evidence
>for cell senescence occuring in vivo has yet been
>obtained.
>  References:
>    Warner, H.R. et al. (1992) Control of Cell
>      Proliferation in Senescent Cells.  Journal
>      of Gerontology 47(6):B185-B189.
>
>1. DNA synthesis inhibition
>       In an expression screen for cDNAs (expressed44
>
>       genes) in senescent cells which could inhibit
>       DNA synthesis in "young" cells, the SDI-1 gene
>       was cloned and found to be significantly up-regulated
>       in senescent cells compered with their young
>       counterparts.  The gene was also cloned by
>       two other groups simultaneously using completely
>       different methods, and is thought to be the
>       primary element responsible for p53-dependent
>       cell-cycle arrest.
>         References:
>         Hunter, Tony (1993) Braking the cycle (minireview).
>             Cell 75:839-841 (Dec 3 '93).
>
>2. complementation studies:
>       Cultured cells can be fused to one another and
> genetic properties analyzed in a manner analagous
> to yeast mating.  Early cell fusion experiments
>clearly illustrated that senescence was a dominant
>       trait in fused cultured cells (i.e. fusions of young to
>senescent are senescent; immortal to senescent are8
>
>senescent.)  This suggested that element(s) were
>missing from immortal cells which could be provided
>by senescent cells.  To determine if immortal cells
>were all lacking the same thing or had different
>deletions, various immortal cells were fused, and
>it was found that some complemented (rescued)
>each other.  In a specific case, a single inserted
>chromosome was sufficient to restore senescence.
>These complementation studies have recently been
>challenged, with apparently different results
>obtained using somewhat different methods.
> References:
>   Pereira-Smith, O.M. & Smith, J.R. (1988) Genetic
>             analysis of indefinite division in human
>      cells:  Identification of four complementation
>      groups.  PNAS 85:6042-6046.
>    Ning, Y. et.al.  (1991) Genetic analysis of
>      indefinite division in human cells:  Evidence
>      for a cell-senescence-related gene(s) on
>      human chromosome 4.  PNAS 88:5635-5639.  52
>
>    Ryan, P.A. et al (1994) Failure of Infinite Life
>      span human cells from different immortality
>      complementation groups to yield finite life
>      span hybrids.  J. Cell. Phys. (in press)
>
>2. vs. DNA damage:
>[The fact that senescence is a dominant property
>suggests that DNA damage is not responsible for
>the senescence phenomenon.  If senescent cells had
>lost a function that immortal cells retained,
>then immortality would be dominant.
>It seems unlikely that senescence would be due
>to a gain of function mutation in all senescent
>cells simultaneously.  If immortality were due
>primarily to a gain of function mutation not present in
>senescent cells, again immortality would be
>expected to dominate.  The remaining possibility
>then is that immortality is due to a loss of function,
>and that senescent cells have retained the normal
>genotype.]  6
>3. telomere shortening:
>It was originally observed by Crick around
>1960 (I think) that the DNA replication machinery,
>which can only synthesize in one direction, would
>       always leave a little bit of unreplicated DNA
>on the lagging strand at the telomere (end of the
>chromosome).  Proteins were identified which could
>extend telomeres, which have a special sequence.
>It is now well established that human telomeres
>get shorter on average as a function of age, that
>they are elongated in sperm cells, that as
>cells senesce in culture their telomeres shorten with
>a striking uniformity.  It has been proposed that
>telomere shortening is responsible for cell
>ce and hence is involved in the aging
>process, but no causal role has emerged.
>Evidence against the telomere hypothesis:  Telomere
>shortening in yeast leads to cell death, not
>the phenotype seen in mammalian cell senescence;9
>
>Mouse telomeres are up to ten times as long as
>       human telomeres and do not shorten over the
>lifetime, and yet mouse cells senesce faster
>that human cells in culture.
>
>References:
>  Kipling, D. & Cooke, H.J. (1990) Hypervariable
>    ultra-long telomeres in mice.  Nature 347:400-402.
>  Lundblad, V. & Szostak, J. W. (1989) A Mutant
>    with a Defect in Telomere Elongation Leads to
>    Senescence in Yeast.  Cell 57:633-643.
>  Allsopp, R.C. et al. (1992) Telomere Length
>    predicts replicativcapacity of human
>    fibroblasts.  PNAS 89(21):10114-8.
>
>3. senescence of the immune system:
>
>F. Cellular Aging
>
>G. Oxidative Stress Hypothesis64
>
>With the random damage model falling out of favor, the
>free radical theory has evolved into what is termed
>the "oxidative stress hypothesis", which asserts that
>modification and damage to cellular molecules by free
>radicals is capable of altering "genetic programs" and
>disrupting cell function, thereby contributing to aging
>regardless of DNA damage.  This model draws
>support from observations that (1) the free hydroxyl
>radical can clearly contribute to biochemical pathways
>producing not only damaged DNA but
>dysfunctional and/or deleterious
>proteins and lipids; (2) levels of such "oxidative stress"
>have been illustrated to increase throughout the lifespans
>of humans and drosophila [ and c. elegans? ], and is
>consistent with the results of rodent dietary restriction;
>(3) there is a clear correlation
>between lifespan and oxygen consumption/body weight
>        weight in a number of species; (4) recent work in
>drosophila has extended lifespan by manipulating the
>        biochemical pathway which metabolizes superoxide and hydrogen7
>
>peroxide.  There is extensive literature on oxidative stress.
>The genes/proteins involved in free radical metabolism are
>well-known (see SOD, catalase, glutathione peroxidase
>in any biochemistry textbook) but their regulation is not
>well understood.  [Enzymes are regulated by their
>substrate and product levels, a "gimme"]
>Downstream events (i.e., exactly which
>important proteins and lipids are modified/damaged) is also
>not clear.
>References:
>  Sohal, R.S. & Allen, R.G. (1990) Oxidative Stress as a
>    causal factor in differentiation and aging: a
>    unifying hypothesis.  Exp. Gerontology 25:499-522.
>  Stadtman, Earl R. (1992) Protein Oxidation and Aging.
>    Science 257:1220-1224.
>
>
>H. DNA methylation
>
>Methylation of cytidine residues of DNA has been correlated  70
>
>with gene expression levels in a number of cases.
>It is unresolved whether methylation is a cause or
>result of altered chromatin structure.  DNA methylation
>is thought to be responsible for imprinting, and
>has been implicated as a mechanism in both
>development and aging.  Overall methylation
>levels in mice apparently decrease
>as a function of age from six to twenty-four
>months, and may subsequently increase.
>There is an extensive literature on DNA methylation
>and aging studies are only a small part of
>this active field.
>References:
>  Singhal, R.P. (1987) DNA methylation in Aging of Mice.
>    Mechanisms of Ageing and Development, 41:199-210.
>
>
>j. Other
>
>III.  Aging in model organisms 3
>
>
>Traditional approaches to genetic and biochemical study
>include making mutants, and fractionating
>extracts and assaying for activity.  Generating
>mutant humans and dissecting them is clearly not
>as ethical, so traditional laboratory organisms are
>used in many aging studies.  This has an advantage
>that experiments can be performed ethically and
>efficiently, but a
>disadvantage that the results may not apply to humans.
>Aside from obvious morpohological differences, perhaps
>the strongest argument is that since humans live so long,
>our genome must have overcome whatever it is that
>causes other organisms to have such short lifespans. On the
>other hand, aging even in fruit flies and worms has a
>striking resemblance to that in humans.
>
>A. Humans
>1. biomarkers of aging in humans:
>7
>
>2. causes of death:  I am having a hard time finding
>               a simple summary of U.S. mortality statistics
>               and would appreciate anyone's contribution
>               here.  What I have found is that approximately
>               40% of all persons will have a neoplasm in
>              heir lifetime and that for about 20% of the
>               population this is the cause of death.  George
>               Will discussed Sherwin B. Nuland's latest book
>               "How We Die:  Reflections on Life's Final Chapter"
>               in the March 7 1994 Newsweek, and claimed that
>               85% of the aging population "succumbs[s] to
>               one of seven ailments - atherosclerosis,
>               hypertension, adult-onset diabetes, obesity,
>               Alzheimer's and other dementias, cancer,
>               and decreased resistance to infections".  The
>               book is apparently quite morbid in its
>attention to detail, and I suppose I will try
>               to find it although I'm frankly not looking
>       forward to reading the thing.82
>
>3. progeroid syndromes:  A number of hereditary disorders
>result in short lifespans during which the
>senescence process is apparently accelerated.
>None of them exactly matches the wild-type
>aging phenotype, but the similarities are
>quite striking, and one would expect genes causing
>these syndromes to be significant in regulating the
>aging process.  Traditional genetic linkage
>analyses are difficult because the diseases are
>very rare autosomal recessive.  A linkage for
>Werner's syndrome was announced two years ago
>but I haven't heard of a gene yet.  A number of
>progeroid syndromes have been linked to
>DNA repair deficiencies, and Werner's has
> reported mutator phenotype.  [The distinction
>etween DNA repair and general transcription
>nd replication is not entirely clear at this
>point.  It is interesting that not all cellular
>mutator phenotypes result in premature aging
>syndromes in the organism.]6
>
>       References:
>  Goto, M. et. al. (1992) Genetic Linkage of Werner's
>    syndrome to five markers on chromosome 8
>    Nature, 355:735-737 (20 Feb '92)
>
>
>4. linkages to longevity:  A recent publication reports
>the distribution of alleles implicated in
>cardiovascular risk at two loci (genes) between
>French centenarians and
>a control population aged 20-70.  The study was
>quite large and different distributions were found
>at both loci.  The paper refers to an established
>linkage between longevity and HLA genotype
>s well.  [Also I believe it is common knowledge
>that women live generally longer than men, making
>the Y chromosome a significant longevity determinant.]
>References:
>  Schachter, F. et. al. (1994) Genetic associations
>    with human longevity at the APOE and ACE loci.9
>
>    Nature Genetics 6:29-32 (january 1994).
>
>5. hormone studies:
>B. Rodents - mice are the most common mammalian experimental
>model for genetic research.  The mouse is
>considered to to fairly closely model humans.
>Murine cells are easily transformed in culture.
>Mice may have fewer defenses against dysplasia
>because they are smaller and don't live as long.
>
>1. calorie restriction:  It was first observed in the
>1930's that rats which were fed less but suppli
>with proper nutrition lived longer.  It has since
>been determined that the caloric intake is the
>sole determinant, suggesting that metabolic rate
>metabolic rate serves as a "genetic clock".  However,
>metabolic rate is not necessarily lowered when the
>reduced mass of the animal is corrected for.  The
>fact that a large number of physiological and     93
>
>pathological symptoms of aging are delayed in CR
>animals has made the phenomenon difficult to
>       study.  As glucose, insulin, and plasma-free
>glucocorticoid concentrations are affected,
>               modulation of neuroendocrine regulatory
>       systems has been implicated.  The onset of tumors,
>       which kill about 50% of all mice, is delayed in
>       CR mice.  No direct evidence
>       exists for any hypothesis regarding the
>       effects of CR.
>References:
>         Masoro, E.J. (1993) Dietary Restriction and Aging.
>    J. of the Am. Ger. Soc. 41:994-999.
>  Weindruch, R. (1989) Dietary Restriction, Tumors,
>    and Aging in Rodents.  J. of Geron. 44(6):67-71.
>
>2. SAM (senescence accelerated mouse):
>3. SOD transgenics
>
>C. Drosophila  6
>
>1. Genetic analysis
>
>2. engineered mutants:  Flies with extra copies of
>both Superoxide Dismutase, which converts
>superoxide anion radical to H2O2, and Catalase,
>which converts H2O2 to water and oxygen, were shown
>to have moderately increased lifespan and
>slightly delayed loss of physical activity.
>Cellular oxidative stress was clearly reduced
>as measured by protein carbonyl content.
>
>References:  Orr, W.C. & Sohal, R.S. (1994)
> Extension of Life-Span by Overexpression of
> Superoxide Dismutase and Catalase in Drosophila
> melanogaster.  Science 263:1128-1130 (25 Feb '94)
>
>D. C. Elegans
>1. backcross analysis
>2. age-1 mutant
>        2. "Methuselah":  A recently reported mutant now holds9
>
>       the record for increase in lifespan.  A mutation
>in daf-2, a developmental gene, more than doubles
>       nematode lifespan (18 to 42 days mean).  The mutants
>are "healthy and fertile".
>References:
>  Kenyon, C. et al. (1993) A C. elegans mutant that lives
>    twice as long as wild type.  Nature 366:461-464.
>      See also News & Views (Pertridge & Harvey)
>      from the same issue.
>
>
>E. Other Species
>
>1. yeast
>2. sea urchin
>3. calorie restriction in primates
>F. Relationship of biomarkers of aging in humans to
>those in model organisms
>
>IV.  Other interesting phenomena, etc.       100%

Reposted by Jan (John) Coetzee

Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=3277