mycophage's Blog Posts

Biogerontology rising: Recent progress in yeast aging research

July 22 2008 / by mycophage / In association with Future Blogger.net
Category: Health & Medicine   Year: General   Rating: 5

(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.)

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Stressor-specific hypersensitivity in the long-lived mole rat

July 11 2008 / by mycophage / In association with Future Blogger.net
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.)

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Hourglass: a blog carnival of biogerontology

July 09 2008 / by mycophage / In association with Future Blogger.net
Category: Health & Medicine   Year: General   Rating: 6 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.)

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Evolutionary theories of aging, as applied to lifespan extension

July 03 2008 / by mycophage / In association with Future Blogger.net
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.)

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Stem cells are wasted on the young: The impact of aging on cell therapy… and potential solutions

June 24 2008 / by mycophage / In association with Future Blogger.net
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.)

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Chronic infection shortens telomeres

May 28 2008 / by mycophage / In association with Future Blogger.net
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.)

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Very small stem cells could help the body repair age-related damage

May 02 2008 / by mycophage / In association with Future Blogger.net
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.)

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A glutamine a day keeps senescence away

April 29 2008 / by mycophage / In association with Future Blogger.net
Category: Health & Medicine   Year: 2008   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.)

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A candle that burns twice as bright and twice as long: the PEPCK-Cmus transgenic mouse

April 28 2008 / by mycophage / In association with Future Blogger.net
Category: Health & Medicine   Year: 2008   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.)

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