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.)
Now, however, there is quantitative evidence to back up that
claim: Smith et al. have used bioinformatic and
genomic approaches to study the conservation between known
longevity genes in yeast and worm, and they show that yeast mutants
in worm longevity genes are significantly more likely to be
long-lived than randomly chosen mutants — suggesting that
genes that modulate aging have been conserved not only
in sequence, but also in function, over a billion years of
evolution.
Given this functional conservation, it is reasonable to use
yeast to help answer questions about aging in general, so long as
these questions as cell-biological in scope.
For instance: NAD+/NADH ratios are
thought to be an important metric of the cellular energy balance,
and appear to have effects both within the mitochondria and the
cytosol. The mitochondrial inner membrane, however, is impermeable
to both NAD+ and NADH. How, then, is information about energy balance
communicated between the two cellular compartments? Easlon et
al. report that two components of the malate-aspartate
NADH shuttle (which transports
metabolites across the mitochondrial membrane, resulting in
equilibration of the cytosolic and mitochondrial NAD+/NADH pools) are involved in controlling
longevity. The two proteins, Mdh1 and Aat1, are required for
longevity enhancement by calorie restriction (CR), and
overexpression of both proteins can increase lifespan independent
of caloric conditions (but in a Sir2-dependent manner, about which
see more below).
Another outstanding question involves how cellular energy
balance is coordinated with the rates of catabolic and anabolic
processes, and how this coordination impinges on regulation of
longevity. We know that in yeast, the effects of CR are mediated by
pathways involving the
nutrient sensor TOR and the kinase
Sch9. (Brief aside: longevity-enhancing mutations of Sch9 can
also
suppress genomic instability; new results from Qin
et al. show that genomic instability is also associated
with lifespan variation in yeast). Sch9 regulates, among other
things, ribosome biogenesis; both CR and Sch9 mutation cause
ribosome synthesis to decrease — but are the ribosome and longevity
phenotypes related? Very likely yes: Steffen et
al. report that multiple means of downregulating ribosome
synthesis all extend lifespan, implying that reducing production of
ribosomes is essential in order to reap the benefits of CR.
As the tools of biology have adapted, so has the yeast field
(sometimes leading the charge, as in the case of the earliest
microarray-based expression profiling experiments).
Murakami et al. have developed a high-throughput method
for measuring yeast lifespan. In this first report, the authors
primarily demonstrate the use of their method on known mutants,
arguing that their results are similar but with lower variance.
(Brief aside: they also demonstrate that CR-induced lifespan
extension does not require SIR2 or any
other yeast sirtuin, adding fuel to the controversy about whether
sirtuins play any role in CR in yeast; for more, see
here and
here.) The increased precision of their technique will allow
detection of subtler aging-related phenotypes than were previously
detectable, very likely allowing us to add to the list of genes
known to regulate lifespan. The high-throughput aspects of the
method, of course, open the door to testing small-molecule drugs
that could delay aging in yeast —
historically a fruitful approach though not without its
potential pitfalls.
If you’ve made it this far, feel free to toast S.
cerevisiae, perhaps with a beer.
(Before I depart, I just want to mention — since it’s not
necessarily clear from the first authors’ names — that four of the
papers mentioned above, as well as many of the papers described in
earlier Ouroboros posts linked above, are the result of the
combined work of the Kaeberlein and
Kennedy
labs at U-Wash Seattle. Both of them worked together in the
Guarente lab
back in the day, and they’ve been in the yeast aging field from its
very beginning. Clearly, their combined work is continuing to
advance the field.)
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