July 22 2008 / by mycophage
Category: Health & Medicine Year: General Rating: 4
(cross-posted from
Ouroboros: Research in the biology of aging)
Our understanding of aging in animals owes a great debt to a
large body of careful work in a single-celled organism, the
brewer’s yeast Saccharomyces cerevisiae. Indeed, as I’ve
argued
before, yeast is one of the two organisms with the strongest
credible claim to have started modern biogerontology. An unusually
large crop of yeast aging papers have appeared over the last few
months, and I thought it would be appropriate to spend a few
paragraphs describing them — in honor of this humble organism that
rises our bread, ferments our beer, and has done so much to open
our eyes to the fundamental mechanisms of aging.
For those unfamiliar with the yeast field or simply wishing a
clearly written and nearly comprehensive summary, Steinkraus et al. provide the historical
perspective. The piece thoroughly reviews the development of yeast
as a model system in aging, as well as the arguments in favor of a
connection between results in yeast and well-established (but
sometimes hard-to-test) hypotheses in animals.
Based on the influence that yeast has already had on
biogerontology as a whole, it seems fair to claim that it will
continue to reveal fundamentals of aging that are conserved across
evolution. (cont.)
Read More
July 11 2008 / by mycophage
Category: Health & Medicine Year: General Rating: 7 Hot
(cross-posted from
Ouroboros: Research in the biology of aging)
Stress resistance at the cellular level is correlated with
longevity at the organismal level, to such an extent that one can
screen for longevity mutants by first identifying
stress-resistant animals. Conversely, the cells of prematurely
aging mutants tend to be
hypersensitive to stress. The idea here is that longevity is
controlled in part by basal and inducible molecular defenses like
antioxidants and chaperones, and that high levels of such factors
confer both stress resistance and enhanced longevity.
What’s interesting about this pattern is that it seems to apply
to a wide range of multiple stresses, with very different physical
bases: oxidation, irradiation, starvation, heavy metal toxicity,
and temperature, to name a few. Without a great deal of
experimental proof to support it, one can imagine some central
homeostatic integrator of cellular well-being, upon which all
manner of perturbations might impinge and which might in turn
control both the appropriate defensive responses and factors that
determine longevity.
It would therefore come as a surprise if a long-lived organism
turned out to be unusually sensitive to stress — and in particular,
sensitive to particular stresses. In one fell swoop, this
would falsify both the general, well-accepted correlative pattern
(stress resistance = longevity) and the somewhat more fanciful
model of a central homeostatic integrator.
align=”right” width=”100”>Lo, the naked mole rat,
Heterocephalus glaber. A eusocial rodent roughly
intermediate in size between a mouse and a rat (depending on where
you shop), and slightly less aesthetically pleasing than an
overcooked boudin blanc with teeth, the naked mole rat has
recently drawn the attention of model-hungry biogerontologists
worldwide: Perhaps because of the
quirky selection pressures on eusocial animals, H.
glaber is unusually long-lived compared to animals of similar
size and body plan (like mice and rats). Like, ten times
longer-lived. So, compared to mice and rats, mole rats should be
much more resistant to all stresses, right? (cont.)
Read More
July 09 2008 / by mycophage
Category: Health & Medicine Year: General Rating: 5 Hot
(cross-posted from
Ouroboros: Research in the biology of aging)
Welcome to the first installation of Hourglass, a blog carnival
devoted to the biology of aging. This first issue corresponds with
the second blogiversary
of Ouroboros, but mostly I consider it a
celebration of the excellent (and growing) community of
bloggers who are writing about biogerontology, lifespan extension
technologies, and aging in general.
Without further ado, then, let’s get started:
Reason at Fight Aging! reports on AnAge, a
curated database of longevity, aging, and life history in a wide
range of animals. The database contains information about average
and maximum longevity within species, and also cool features like
lists of the “world-record” holders for the longest-lived organisms
on the planet. AnAge will be a great tool for anyone interested in
studying
evolution of negligible senescence or exploiting
lifespan diversity across related species to learn about
mechanisms of aging. For those who are interested in databases of
this kind, AnAge is a component of a larger project, the Human Ageing Genomic
Resources.
The most widely studied technique for
extending the lifespan of diverse animals is calorie restriction (CR),
whose benefits in humans are still under careful study. One of the
disadvantages of studying humans, of course, is that you can’t keep
them in completely controlled environments, free from temptation to
cheat on their defined diets — but this may be more than adequately
compensated by the main advantage of human subjects, namely, that
they can tell you how they’re feeling about the study while it’s
underway. Over at Weekly Adventures
of a Girl on a Diet, Elizabeth Ewen describes
her experiences as a subject in the CALERIE study, a large-scale test of the effects
of CR on humans (we’ve discussed CALERIE
here before). In her post, Elizabeth describes the CALERIE study in detail, and also critically assesses
some of its specific features — something that no mouse, however
talented, could ever do. (cont.)
Read More
July 03 2008 / by mycophage
Category: Health & Medicine Year: General Rating: 4 Hot
(cross-posted from
Ouroboros: Research in the biology of aging) 
Prominent biogerontologist and evolutionary biologist Michael Rose
(recently named the
chief scientific officer of the Biogerontology Research Foundation)
has reviewed the decades-old interplay between evolutionary
theories of aging and efforts to extend animal lifespans.
In the article, Rose critically evaluates several of the
assumptions underlying
SENS (Strategies for Engineered Negligible Senescence)
as formulated by anti-aging activist Aubrey de Grey,
placing them in the context of demographic and
population-biological observations. Ultimately, Rose concludes that
life-extension therapeutics must address the issue of age-specific
adaptation in order to be effective (link;
emphasis below is mine):
Making SENSE: Strategies for
Engineering Negligible Senescence Evolutionarily
Thirty years ago, in 1977, few biologists thought that it would
be possible to increase the maximum life span characteristic of
each species over the variety of environmental conditions in which
they live, whether in nature or in the laboratory. But the
evolutionary theory of aging suggested otherwise. Accordingly,
experiments were performed with fruit flies, Drosophila
melanogaster, which showed that manipulation of the forces of
natural selection over a number of generations could substantially
slow the rate of aging, both demographically and physiologically.
After this first transgression of the supposedly absolute limits to
life extension, it was suggested that mammals too could be
experimentally evolved to have greater life spans and slower aging.
And further, it was argued that such postponed-aging mammals could
be used to reverse-engineer a slowing of human aging. The
subsequent discovery and theoretical explanation of mortality-rate
plateaus revealed that aging was not due to the progressive
physiological accumulation of damage. Instead, aging is now
understood by evolutionary biologists to arise from a transient
fall in age-specific adaptation, a fall that does not necessarily
proceed toward ineluctable death. This implies that SENS must be based on re-tuning adaptation, not
repairing damage. As evolutionary manipulation of model
organisms shows us how adaptation can be focused on engineering
negligible senescence, there are thus both scientific and practical
reasons for making SENS evolutionary;
that is making SENSE.
(cont.)
Read More
June 24 2008 / by mycophage
Category: Health & Medicine Year: General Rating: 5 Hot
(Cross-posted from Ouroboros: Research in the
biology of aging)
One major barrier to the therapeutic use of pluripotent and
totipotent cells is that by the time a patient needs them, their
body has become less able to use them. 
The stem cell niche (i.e., those factors in the tissue
microenvironment that stem cells require in order to function
normally) changes with age, and not for the better: for example,
embryonic stem cells
lose proliferative capacity when confronted with aged
niches.
This appears to be a general problem in metazoans, and is
conserved between humans and relations as distant as arthropods —
fortunately for us, because it means that the tools and genius of
the Drosophila community can be brought to bear on the
problem. In the fruit fly, age-related changes in the stem cell
niche are well-documented, especially in the reproductive system,
and the molecular players are starting to be individually
identified (see our previous post on
Dpp, this one on
BMP, unpaired and cadherins,
and this nice
review of the whole story). There are one or two tissues in
which stem cells actually become
more numerous with age, but the consensus seems to be that the
aged microenvironment is generally not beneficial for stem cells.
At least in the fly. (cont.)
Read More
May 28 2008 / by mycophage
Category: Health & Medicine Year: General Rating: 8 Hot
(Cross-posted from
Ouroboros: Research in the biology of aging)
Chronic stress has been associated with decreased telomere
length in lymphocytes. The association is robust and has been
observed in multiple studies, including one that looked at stress
in addition to other risk factors for
cardiovascular disease (CVD), so it appears that lymphocyte
telomeres are a useful biomarker for some convolution of age and
lifetime stress level. 
The question still remains, however, whether the relationship
is correlative or causative. Do stress and other lifestyle factors
somehow cause shortened telomeres, or are the two phenomena
otherwise-unrelated indications of some common underlying
cause?
One of the “trivial” explanations for a causative relationship,
usually advanced by critics who aren’t particularly impressed by
the initial findings, is that stressed-out or otherwise unhealthy
people are more vulnerable to infection than their serene, healthy
counterparts. Chronic infection requires increased production of
lymphocytes, which overworks the stem cell compartment from which
these cells are derived; increased cell divisions leads to
decreased telomere length — a perfectly satisfactory explanation
for the observation.
If that is true, then chronic infection in the absence of
lifestyle risk factors should cause telomere shortening on its own
(let’s stipulate for the moment that stress increases
susceptibility to disease, an idea supported by my own anecdotal
experience of college finals). Ilmonen et
al. have demonstrated that this is indeed the case, at
least in mouse: (cont.)
Read More
May 02 2008 / by mycophage
Category: Health & Medicine Year: General Rating: 8 Hot
(Cross-posted from
Ouroboros: Research in the biology of aging)
It is widely accepted that stem cells are involved in tissue
regeneration. It is also widely accepted that (in most organs) stem
cells are vanishingly rare. So: if there doesn’t happen to be a
stem cell adjacent to a site of damage, how can stem cells be
involved in the process of tissue repair?
One possible answer: There might be more stem cells than we
think, because we’ve been missing them for some reason. This
possibility (”both”) is strongly supported by the recent findings
of Zuba-Surma et al., who have discovered a
population of tiny pluripotent cells (termed, appropriately, very
small embryonic-like, or VSELs) scattered throughout the body.
Very small embryonic-like stem cells in adult
tissues—Potential implications for aging
Recently our group identified in murine bone marrow (BM) and
human cord blood (CB), a rare population of very small
embryonic-like (VSEL) stem cells. We hypothesize that these cells
are deposited during embryonic development in BM as a mobile pool
of circulating pluripotent stem cells (PSC) that play a pivotal
role in postnatal tissue turnover both of non-hematopoietic and
hematopoietic tissues.(cont.)
Read More
April 29 2008 / by mycophage
Category: Health & Medicine Year: 2008 Month: Apr Rating: 9 Hot
(Cross-posted from
Ouroboros: Research in the biology of aging)
Cellular senescence is regarded as a tumor suppressor mechanism:
damaged cells permanently leave the cell cycle (preventing tumor
initiation), and also secrete factors that trigger both tissue
repair and inflammation in the vicinity. This is probably good at
first but bad later on: persistent senescent cells also secrete
growth factors and metalloproteases that degrade the tissue
microenvironment and encourage nearby preneoplastic cells to
progress into full-blown tumors. Thus, senescence has been
implicated in late-life cancer and age-related decline in tissue
function.
The “damage” in question is usually genotoxic in nature:
telomere shortening, indicating that a cell has undergone many
rounds of potentially mutagenic cell division, or high levels of
DNA damage such as that resulting from
ionizing radiation or exposure to chemical clastogens. Oncogene
expression probably also induces senescence via DNA damage, by triggering over-firing of replication
origins and generating broken ends and weird chromatin structures
that are interpreted as damage.
Now it appears that falling cellular ATP levels may also result in cellular senescence.
Unterluggauer et al. report that inhibition of
glutaminolysis (preventing cells from generating ATP from glutamine, an unglamorous and occasionally
overlooked pathway that is nonetheless an important energy source
in many cellular lineages) results in increased senescence in human
vascular endothelial cells (HUVECs): (cont.)
Read More
April 28 2008 / by mycophage
Category: Health & Medicine Year: 2008 Month: Apr Rating: 9 Hot
(Cross-posted from
Ouroboros: Research in the biology of aging.)
A transgenic mouse that lives twice as long as controls is also
stronger and faster, arguing against the idea of inherent negative
tradeoffs associated with lifespan extension. 
Increased expression of a metabolic enzyme, phosphoenolpyruvate
carboxykinase (PEPCK, an enzyme that most of us learned about in
freshman biology and then promptly forgot, reasoning that the
descriptive name and the ability to look it up if necessary would
suffice if it ever came up again) results in mice that are
muscular, have lower body fat than a runway model, and able to run
25 times farther than a wildtype control.
Even more interesting, according to proud parents Hanson and Hakimi, the females of the PEPCK-Cmus strain mate and have
normal-sized litters at 35 months, an age when the blood of
wildtype mice has cooled substantially (and, indeed, the mice
themselves are starting to check out). The implication is that
aging is slowed, and longevity extended, as a result of the
transgene.
It’s become reflexive to ask whether a long-lived mutant is
living longer because it’s calorie-restricted for some reason,
incidental to the main phenotype conferred by the mutation, but
this is not the case here: In order to preserve their enviable
bods, PEPCK-Cmus mice eat 60%
more than controls — so they’re not extending their lifespan
by dieting. If anything, they’re anti-dieting: their increased
metabolic efficiency means they’re harvesting more calories per
gram of carb or fat than normal animals. No word yet on what
happens if you do try to calorie-restrict them; I can imagine it
going either way but am holding out hope for tiny
explosions. (cont.)
Read More
